Highlights

Screening for Sickle Cell Disease

The United States Preventive Services Task Force’s 2007 guidelines recommend that all newborn infants be screened for sickle cell disease. (In the United States, most states require hospitals to perform this test.) Early detection of sickle cell disease ensures that babies will be given treatment to prevent infections. Sickle cell disease is an inherited condition. About 1 in 375 African-American babies are born with sickle cell disease, but children of other ethnicities are also at risk.

Infections and Sickle Cell Disease

• Children with sickle cell disease are highly susceptible to many life-threatening infections, including those caused by the pneumococcus bacterium. Pneumococcal vaccinations are an important protection against this bacterium. Research published in 2007 in Clinical Infectious Diseases indicates that the introduction of the pneumococcal conjugate vaccine has helped reduce by 90% the rate of pneumococcal infections in children with sickle cell disease. Four doses of this vaccine are given from age 2 - 15 months. A second type of pneumococcal vaccine, pneumococcal saccharide, is given when the child reaches 2 years of age.
• Daily antibiotics given from age 2 months through 5 years can help prevent many other types of bacterial infections, such as meningitis and blood infections.

Introduction

Blood has two major components:

• Plasma is a clear yellow liquid that contains proteins, nutrients, hormones, electrolytes, and other substances. It constitutes about 55% of blood.
• White and red blood cells and platelets make up the balance of blood. The white cells are the infection fighters for the body, and platelets are necessary for blood clotting. The important factors in anemia, however, are red blood cells.

Red blood cells (RBCs), also known as erythrocytes, carry oxygen throughout the body to nourish tissues and sustain life. Red blood cells are the most abundant cells in our bodies. Men have about 5.2 million red blood cells per cubic millimeter of blood, and women have about 4.7 million red blood cells per cubic millimeter of blood. To understand red blood cells and their role in anemia, it is useful to know certain facts about them.

Hemoglobin and Iron. Each red blood cell contains about 280 million hemoglobin molecules. Hemoglobin is a complex molecule and the most important component of red blood cells. It is composed of protein (globulin) and a molecule (heme), which binds to iron.

In the lungs, the heme component binds to oxygen in exchange for carbon dioxide. The red blood cells carry the oxygen to the body's tissues, where the hemoglobin releases the oxygen in exchange for carbon dioxide, and the cycle repeats. The oxygen is used in the mitochondria, the power source within all cells.

Structure and Shape. Red blood cells are extremely small and look something like tiny, flexible inner tubes. This unique shape offers many advantages:

• It provides a large surface area to absorb oxygen and carbon dioxide.
• Its flexibility allows it to squeeze through capillaries, the tiny blood vessels that join the arteries and veins.
• Abnormally shaped or sized erythrocytes are typically destroyed and eliminated.

Blood Cell Production (Erythropoiesis). The actual process of making red blood cells is called erythropoiesis. (In Greek, erythro means "red" and poiesis means "the making of things.") The process of manufacturing, recycling, and regulating the number of red blood cells is complex and involves many parts of the body:

• The body carefully regulates its production of red blood cells so that enough are manufactured to carry oxygen but not so many that the blood becomes thick or sticky (viscous).
• Most of the work of erythropoiesis occurs in the bone marrow.
• If the body needs more oxygen (at high altitudes, for instance), the kidney triggers the release of erythropoietin (EPO), a hormone that increases production of red blood cells in the bone marrow.
• The lifespan of a red blood cell is 90 - 120 days. The liver and spleen remove old red blood cells from the blood.
• When old red blood cells are broken down for removal, iron is returned to the bone marrow to make new cells.

Sickle cell disease occurs from genetic changes which causes a portion of the hemoglobin molecules to be abnormal:

• Hemoglobin A (HbA). HbA is the hemoglobin molecule found in normal red blood cells during childhood and adulthood. People without sickle cell anemia have primarily this type of hemoglobin in their blood cells.
• Hemoglobin S (HbS). HbS (S is for sickle) is the abnormal variant of hemoglobin A, which occurs in sickle-red blood cells and is the primary characteristic of the disease. The difference between hemoglobin A (HbA) and hemoglobin S (HbS) lies in only one protein out of about 300 that are common to both. This protein lies along an amino-acid chain called beta-globin, where even a tiny abnormality has disastrous results.

Hemoglobin is the most important component of red blood cells. It is composed of a protein called heme, which binds oxygen. In the lungs, oxygen is exchanged for carbon dioxide. Abnormalities of an individual's hemoglobin value can indicate defects in red blood cell balance. Both low and high values can indicate disease states.

Hemoglobin F (HbF) is a form of hemoglobin that is produced during fetal development in the womb. (The F in HbF stands for fetal.) It is usually present for only a short time after birth. Normally, most HbF is later replaced by HbA, although some HbF may persist throughout life. Importantly, HbF is able to block the sickling action of red blood cells. Infants who have inherited sickle cell disease do not develop symptoms of the illness while they still have HbF present in their blood. People with the sickle cell gene who continue to carry some fetal hemoglobin are better protected, therefore, from severe forms of the disease. This knowledge is being used as the basis for therapies used in treating sickle cell disease.

The symptoms and problems of sickle cell disease are a result of the hemoglobin S (HbS) molecule:

• When the sickle hemoglobin molecule loses its oxygen, it forms rigid rods called polymers that change the red blood cells into a sickle or crescent shape.
• These abnormally sickle-shaped cells are both rigid and sticky. They stick to the walls and cannot squeeze through the capillaries. Blood flow through tiny blood vessels becomes slowed or stopped throughout the body. This deprives tissues and organs of oxygen.
• In the immediate setting, oxygen deprivation (hypoxia) can cause severe pain (the sickle cell crisis). Over time, it leads to gradual destruction in organs and tissues throughout the body.

Click the icon to see an image of sickle cells.

• In a vicious cycle, oxygen deprivation in cells leads to more polymerization and increased production of sickle cells. The higher the concentration of sickle hemoglobin and the more acidic the environment, the faster the sickle cell process.
• Cell dehydration (not enough water molecules) is another major destructive factor in the sickling process of red blood cells. Dehydration increases the density of hemoglobin S within the cell, thereby speeding up the sickling process.
• Sickle cells also have a shorter life span (10 - 20 days) than that of normal red blood cells (90 - 120 days). Every day the body produces new red blood cells to replace old ones, but sickle cells become destroyed so fast that the body cannot keep up. The red blood cell count drops, which results in anemia. This gives sickle cell disease its more common name, sickle cell anemia.

The severity of sickle cell disease generally depends on a number of factors:

• The extent of oxygen loss. Prolonged oxygen deprivation contributes to the severe pain experienced as a sickle cell crisis. It also produces both short- and long-term organ damage. The lungs are specifically critical targets of the disease process. Because they supply oxygen, they can restore the sickle molecules to a normal form. Unfortunately, once the process occurs, the lungs become major sites for sickle cell damage, particularly for dangerous acute episodes of chest pain.
• The acidity of the environment. The lower the better. The organs most seriously affected are those with an acidic environment (such as the spleen and bone marrow).
• The concentration of hemoglobin S within the cell. The lower the better.
• The amount of a protective hemoglobin F (for fetal). The more the better.

Risk Factors

Sickle cell disease is inherited. People at risk for inheriting the gene for sickle cell descend from people who are or were originally from Africa and parts of India and the Mediterranean. The sickle cell gene also occurs in people from South and Central America, the Caribbean, and the Middle East. The high incidence of the sickle cell gene in these regions of the world is due to the sickle cell's ability to make red blood cells resistant to the malaria parasite:

• People who inherit just a single gene are referred to as having the sickle trait. These people are protected against malaria and do not develop sickle cell disease. About 40% of people in certain parts of Africa and about 9% of African-Americans have the trait.
• Those who inherit both copies of the HbS gene develop sickle cell disease. They are not protected from malaria, however. In fact, malaria is more serious in these individuals. An estimated 1 in 500 African-Americans and 1 in 1,000 - 1,400 Hispanic Americans are born with sickle cell disease.

The sickle cell gene for hemoglobin S (HbS) is the most common inherited blood condition in America. About 72,000 Americans -- mostly African-Americans -- have sickle cell disease. The risk for inheriting sickle cell disease from parents with the sickle cell gene is as follows:

• One parent has only one copy of the sickle cell gene and the other parent has two normal hemoglobin genes, and the child inherits a healthy gene from each parent. The child will not inherit either the disease or the trait.
• The child inherits one copy of the sickle cell gene. The child has the trait (HbS) only. The other, healthy hemoglobin gene overrides HbS and blocks the development of sickle cell disease. Such people lead normal lives.
• The child inherits the hemoglobin S gene from both parents (HbSS). The child develops the full-blown disease. (If each parent has one copy of the gene, the child has a 25% chance of acquiring the disease.)
• The child inherits one hemoglobin S gene and one abnormal hemoglobin gene from other causes (such as one form called HbSC). Such children may develop a form of sickle cell disease. It is often a milder variant, but children can experience severe symptoms. They are also at risk for some of the complications of sickle cell disease, although their risks for serious problems are lower than in children with the full-blown disease.

Symptoms

General Symptoms in Infants. In infants, symptoms do not usually appear until late in the baby's first year. Most commonly, they include:

• Fever
• Swelling of the hands and feet
• Pain in the chest, abdomen, limbs, and joints
• Nosebleeds and frequent upper respiratory infections

General Symptoms in Childhood. Pain is the most common complaint. It can be acute and severe or chronic, usually from orthopedic problems in the legs and low back. Other symptoms include:

• Anemia
• Fatigue
• Irritability
• Jaundice (yellowish discoloration of the skin and eyes)
• Bedwetting

Additional Symptoms in Adolescence or Adulthood. Symptoms of childhood continue in adolescence and adulthood. In addition, patients may experience:

• Delayed puberty (in young teenagers)
• Severe joint pain
• Progressive anemia
• Leg sores
• Gum disease

The hallmark of sickle cell anemia is a group of devastating symptoms known collectively as a sickle cell crisis (also sometimes known as a vaso-occlusive crisis). Sickle cell crises are episodes of pain that occur with varying frequency and severity in different patients and are usually followed by periods of remission. Severe sickle cell pain has been described as being equivalent to cancer pain and more severe than postsurgical pain. It most commonly occurs in the lower back, leg, abdomen, and chest, usually in two or more locations. Episodes usually recur in the same areas.

The risk for a sickle cell crisis is increased by any activity that boosts the body's requirement for oxygen, such as illness, physical stress, or being at high altitudes. In more than half the cases, however, the trigger is unknown. Acute chest syndrome is a particularly serious complication of sickle cell crisis. It occurs in the lungs and can be extremely serious and even life threatening.

Diagnosis

Prenatal diagnosis of sickle cell disease is now possible for women who may be at risk for having a child with the disease. A positive result for sickle cell disease, however, poses extremely difficult questions even for parents who are not opposed to abortion.

A genetic test known as preimplantation genetic diagnosis (PGD) may prove to determine the presence or absence of the sickle cell mutation in embryos (fertilized eggs) before they are implanted in the mother during assisted fertilization techniques. This genetic tool may eventually help avoid the often emotionally devastating effects of abortion.

In the United States, most hospitals screen newborn babies for sickle cell disease. To perform the test, a blood sample is taken from the baby's heel using a simple needle prick. Early detection of sickle cell disease can help reduce the risk for life-threatening infections and increase the odds for survival. Babies who are diagnosed with sickle cell disease are given daily antibiotics to help prevent infections.

Unfortunately, no tests can definitely determine which children are at highest risk for a stroke and, therefore, would be candidates for ongoing blood transfusions. The following are diagnostic tools currently used or under investigation:

• Transcranial Doppler (TCD) ultrasonography measures the speed of blood flow in the brain and is the most sensitive method to date for identifying children at risk for stroke. However, high-risk children are still vulnerable to stroke even if the TCD screening diagnosed normal blood flow velocities.
• The use of follow-up magnetic resonance imaging (MRI) to detect small blockages in blood vessels may help confirm high risk in patients identified by TCD ultrasound.
• Some patients may need to undergo angiography, an invasive diagnostic technique useful for detecting aneurysms.
• Researchers are also beginning to uncover possible genetic markers that may eventually be used to help identify sickle cell patients at higher risk for stroke.

Outlook

New and aggressive treatments for sickle cell disease are prolonging life and improving its quality. As recently as 1973, the average lifespan for people with sickle cell disease was only 14 years. Currently, life expectancy for these patients can reach 50 years and over. Early studies showed that women had a greater risk for death from sickle cell disease than men, but experts now believe this was due to high mortality during pregnancies before the mid-1970s. Women with sickle cell disease now actually live longer than their male counterparts.

The damage and durability of sickle cell disease occurs because the logjam that sickle cells cause in the capillaries slows the flow of blood and reduces the supply of oxygen to various tissues. Not only does pain occur when body tissues are damaged by lack of oxygen, but serious and even life-threatening complications can result from severe or prolonged oxygen deprivation. Sickle cell disease is referred to in some African languages as "a state of suffering," but the disease has a wide spectrum of effects, which vary from patient to patient. In some people, the disease may trigger frequent and very painful sickle cell crises that require hospitalization. In others, it may cause less frequent and milder attacks.

Children with sickle cell disease are very susceptible to infections, usually because their damaged spleens are unable to protect the body from bacteria. A recent study suggested that signs of impaired lung function occur even in very early years. As medical progress has increased the lifespan of children with sickle cell disease, older patients are now facing medical problems related to the long-term adverse effects of the disease process. The most serious dangers are acute chest syndrome, long-term damage to major organs, stroke, and complications during pregnancy such as high blood pressure in the mother and low birth weight.

Complications

There is still no cure for sickle cell disease other than experimental transplantation procedures, but treatments for complications of sickle cell have prolonged the lives of many patients who are now living into adulthood.

The hallmark of sickle cell disease is the sickle cell crisis (also sometimes known as a vaso-occlusive crisis), which is an episode of pain. It is the most common reason for hospitalization in sickle cell disease. The pattern may occur as follows:

• In general, the risk for a sickle cell crisis is increased by any activity that boosts the body's requirement for oxygen, such as illness, physical stress, or being at high altitudes. In more than half of episodes, however, the trigger is unknown.
• Episodes typically begin at night and last 3 - 14 days, accelerating to a peak over several days and then declining.
• The pain is typically described as sharp, intense, and throbbing. Severe sickle cell pain has been described as being equivalent to cancer pain and more severe than postsurgical pain. Shortness of breath is common.
• Pain most commonly occurs in the lower back, leg, hip, abdomen, or chest, usually in two or more locations. Episodes usually recur in the same areas. Pain in the bones (usually occurring symmetrically on both sides) is common because blood obstruction can directly damage bone and because bone marrow is where red blood cells are manufactured.
• The liver or spleen may become enlarged, causing pain in the upper right or upper left sides of the abdomen. Liver involvement may also cause nausea, low-grade fever, and increasing jaundice.
• Males of any age may experience prolonged, often painful erections, a condition called priapism.

Episodes cannot be predicted, and they vary widely among different individuals. In one study, nearly 40% of patients reported no painful episodes over a 5-year period. About 5% of patients experienced severe and frequent episodes (more than three a year). They sometimes become less frequent with increasing age. Generally, people can resume a relatively normal life between crises. Most patients are pain-free between episodes although pain can be chronic in some cases.

Acute chest syndrome (ACS) occurs when the lungs are deprived of oxygen during a crisis. It can be very painful, dangerous, and even life threatening. It is a leading cause of illness among sickle cell patients and is the most common condition at the time of death. At least one whole segment of a lung is involved, and the following symptoms may be present:

• Fever of 101.3°F degrees (38.5°C) or above
• Rapid or labored breathing
• Wheezing or cough
• Acute chest pain

Pain often lasts for several days. In about half of patients, severe pain develops about 2 - 3 days before there are any signs of lung or chest abnormalities. Acute chest syndrome is often accompanied by infections in the lungs, which can be caused by viruses, bacteria, or fungi. Pneumonia is often present. A dull, aching pain usually follows, which most often ends after several weeks, although it may persist between crises.

Air is breathed in (inhaled) through the nasal passageways, and travels through the trachea and bronchi to the lungs.

Causes of Acute Chest Syndrome. Primary causes of acute chest syndrome include:

• Infection. Infection from viruses or small atypical organisms (Chlamydia and Mycoplasma) is the most common cause of the oxygen deprivation that leads to acute chest syndrome.
• Blockage of blood vessels. Blockage in the blood vessels (called infarction) that cuts off oxygen in the lungs is another important cause of acute chest syndrome. Blockage may be produced by blood clots or fat embolisms. (Fat embolisms are particles formed from fatty tissue in the bone marrow that enter and travel through the blood vessels.)
• Asthma. Asthma can increase the frequency and pain of acute chest syndrome episodes in children, according to an important 2006 study. The researchers recommended that all children with sickle-cell disease who have frequent acute chest syndrome attacks should be evaluated for asthma.

In about 45% cases, the cause cannot be established. Some cases of acute chest syndrome may result from treatments of the crisis, including from administration of opioids (which reduce oxygen) or excessive use of intravenous fluids. Other lung diseases may also trigger ACS.

Severity of Acute Chest Syndrome. The mortality rates for ACS are around 2% in children and 4% in adults. The syndrome and its long-term complications are the major causes of death in older patients. The condition is four times more deadly in adults than in children. The longer a patient survives, the greater is the damage done by repetitive sickle cell crises in the chest and lungs.

The following destructive effects can occur:

• Damage in the chest area from recurrent episodes increases susceptibility to invading infections, even those that are ordinarily not harmful. Infections frequently clear up if they are limited to small areas of the lung, but if they spread, they can progress very quickly and become life threatening.
• Lung damage over time can lead to obstruction in the airways in lungs, causing asthma-like conditions.

Infections are common and an important cause of severe complications in sickle cell patients. Before early screening for sickle cell disease and the use of preventive antibiotics in children, 35% of infants with sickle cell died from infections. Fortunately, with screening tests for sickle cell now required for newborns in most states, and with the use of preventive antibiotics in babies who are born with the disease, this terrible mortality rate has dropped significantly.

Infections in Infants and Toddlers with Sickle Cell Disease. The most common organisms causing infection in children with sickle cell disease include:

• Streptococcus pneumoniae (can cause blood infections or meningitis)
• Haemophilus influenza (a cause of meningitis)

Such infections pose a grave threat to infants and very young children with sickle cell disease. They can progress to fatal pneumonia with devastating speed in infants, and death can occur only a few hours after onset of fever. The risk for pneumococcal meningitis, a dangerous infection of the central nervous system, is also significant.

Infections in Children and Adults. Infections are also common in older children and adults with sickle cell disease, particularly respiratory infections such as pneumonia, kidney infections, and osteomyelitis, a serious infection in the bone. (The organisms causing them, however, tend to differ from those in young children.) Infection-causing organisms include:

• Chlamydia and Mycoplasma pneumoniae. These are the important infections in acute chest syndrome (see above).
• Gram-negative bacteria. This group of bacteria mostly infects hospitalized patients and can cause serious pneumonias and other infections.

About 30% of patients with sickle cell disease have pulmonary hypertension. Pulmonary hypertension is a serious and potentially deadly condition that develops when pressure in the arteries of the lungs increases. It is an often unrecognized complication and cause of death in sickle cell disease. Many doctors recommend that all adults with sickle cell disease undergo echocardiographic testing to identify if they are at risk for pulmonary hypertension and require treatment.

Researchers are developing new types of tests that may help with early identification of pulmonary hypertension. For example, some studies indicate that a simple blood test for the hormone brain natriuretic peptide (BNP) could help identify patients with sickle cell pulmonary hypertension. Higher levels of BNP are associated with increased pressure in the pulmonary (lung) arteries. A blood test measuring levels of the enzyme lactate dehydrogenase (LDH) may also help identify patients at risk for pulmonary hypertension, as well as leg ulcerations and priapism (persistent and painful erection of the penis). Echocardiography or other tests would still need to be performed to confirm results from these blood tests.

The primary symptom of pulmonary hypertension is shortness of breath, which is often severe. Pulmonary hypertension can be very serious and life threatening in the short- and long-term. If pulmonary hypertension develops suddenly it can cause respiratory failure, which is life threatening. Over time, pulmonary hypertension may cause a condition called cor pulmonale, in which the right side of the heart increases in size. In some cases, this enlargement can lead to heart failure.

Click the icon to see an image of cor pulmonale.

After acute chest syndrome, stroke is the most common killer of patients with sickle cell disease who are older than 3 years old. Between 8 - 10% of patients suffer strokes, typically at about age 7. Patients may also suffer small strokes that may not be immediately noticeable. However, patients who have many of these small strokes may over time start behaving differently or have worsening mental functioning.

Strokes are usually caused by blockages of vessels carrying oxygen to the brain. Patients with sickle cell disease are also at high risk for stokes caused by aneurysm, a weakened blood vessel wall that can rupture and hemorrhage. Multiple aneurysms are common in sickle cell patients, but they are often located where they cannot be treated surgically.

Click the icon to see an image of stroke.

Anemia is a significant characteristic in sickle cell disease (which is why the disease is commonly referred to as sickle cell anemia).

Severe worsening of anemia. Children, adolescents, and possibly young adults may experience what is called splenic sequestration. This happens when a large amount of the sickled red blood cells collect in the patient's spleen. Symptoms may include pain in the right abdomen below the ribs and a large mass (the swollen spleen) may be felt.

Chronic Anemia. Because of the short lifespan of the sickle red blood cells, the body is often unable to replace red blood cells as quickly as they are destroyed. This causes a particular form of anemia called hemolytic anemia. Most patients with sickle cell disease have a hemoglobin levels of 8 g/dL, much lower than people without sickle cell anemia. Chronic anemia reduces oxygen and increases the demand on the heart to pump more oxygen-bearing blood through the body. Eventually, this can cause the heart to become dangerously enlarged, with an increased risk for heart attack and heart failure.

On occasion, patients may experience what is called an aplastic crisis. This happens when the cells in the bone marrow that are normally trying to make new red blood cells suddenly stop working. This sudden stopping is often triggered by a virus called human parvovirus B19.

The kidneys are particularly susceptible to damage from the sickling process. Persistent injury can cause a number of kidney disorders, including infection. Problems with urination are very common, particularly uncontrolled urination during sleep. Patients may have blood in the urine, although this is usually mild and painless and resolves without damaging consequences. Kidney failure is a major danger in older patients and accounts for 10 - 15% of deaths in sickle cell patients. Renal medullary carcinoma is an aggressive, rapidly destructive tumor in the kidney that is rare but can occur as a result of sickle cell disease.

Click the icon to see an image of kidney anatomy.

A reported 38 - 42% of males, including children, with sickle cell disease suffer from priapism. Priapism causes prolonged and painful erections that can last from several hours to days. Experts think that priapism in sickle cell disease may be caused by the destruction of red blood cells and subsequent reduction of nitric oxide. If priapism is not treated, partial or complete impotence can occur in 80% of cases.

Click the icon to see an image of the male reproductive anatomy.

Enlargement of the liver occurs in over half of sickle cell patients, and acute liver damage occurs in up to 10% of hospitalized patients. Because sickle cell patients often need transfusions, they have been at higher risk for viral hepatitis, an infection of the liver. This risk, however, has decreased since screening procedures for donated blood have been implemented.

About 30% of children with sickle cell disease have gallstones, and by age 30, 70% of patients have them. In most cases, gallstones do not cause symptoms for years. When symptoms develop, patients may feel overly full after meals, have pain in the upper right quadrant of the abdomen, or have nausea and vomiting. Acute attacks can be confused with a sickle cell crisis in the liver. Ultrasound is usually used to confirm a diagnosis of gallstones. If the patient does not have symptoms, no treatment is usually necessary. If there is recurrent or severe pain from gallstones, the gallbladder may need to be removed. Minimally invasive procedures (using laparoscopy) reduce possible complications. [For more information, see In-Depth Report #10: Gallstones.]

Click the icon to see an image of cholithiasis.

The spleen of most adults with sickle cell anemia is nonfunctional due to recurrent episodes of oxygen deprivation that eventually destroy it. Injury to spleen causes problems in immune function and increases the risk for serious infection. A very serious anemic condition called acute splenic sequestration crisis (sudden spleen enlargement) can occur if the damaged spleen suddenly becomes enlarged from trapped blood.

Click the icon to see an image of an enlarged spleen.

In some children with sickle cell disease, excessive production of blood cells in the bone marrow causes bones to grow abnormally, resulting in long legs and arms or misshapen skulls. Sickling that blocks oxygen to the bone can also cause bone loss and pain. Sickling that affects the hands and feet of children causes a painful condition called hand-foot syndrome. A condition called avascular necrosis of the hip occurs in about half of adult sickle cell patients when oxygen deprivation causes tissue death in the bone. Eventually adult patients may require surgery to remove diseased and dead bone tissue. Joint replacement may be required in severe cases. X-rays are not very useful for detecting early disease in the bones. MRI may be important.

Click the icon to see an image of the blood supply to bone.

Leg sores and ulcers occur in up to 10% of sickle cell patients and usually affect patients older than 10 years.

Women with sickle cell disease who become pregnant are at higher risk for complications, but serious problems have dropped significantly over the past decades. One study reported a higher risk for premature birth and low birth weight in the baby, and a higher risk for infections and hospital visits in the mother after delivery. Pain crises occurred in nearly half of the women, and nearly 60% required transfusions. The study also reported, however, that, in general, the outcome for pregnancy is favorable. Still, pregnancy during sickle cell is high-risk and carries a mortality rate of about 1%.

Older children and adult patients with sickle cell are subject to other medical problems, including impaired physical development, gum disease, and scarring and detachment of the retina.

Treatment

Research is ongoing toward identifying the biologic and chemical activities that promote or protect against the sickle cell process. Currently, experimental treatments focus on the basic processes that cause the red blood cells to sickle in the first place. There are three basic modes of treatment:

• Stimulation of production of healthy fetal hemoglobin in order to inhibit the sickling process
• Blocking dehydration in the cells
• Transplantation of bone marrow or stem cells from healthy donors so that normal hemoglobin is produced rather than hemoglobin S

Hemoglobin F (HbF), also called fetal hemoglobin, is the form of hemoglobin in the fetus and small infants. Most HbF is later replaced by the hemoglobin that is present in the growing child and adult, although some HbF may persist. Fetal hemoglobin is able to block the sickling action of red blood cells so that infants with sickle cell disease do not develop symptoms of the illness while they still have hemoglobin F. Adults who have sickle cell disease but still retain high levels of hemoglobin F generally have mild disease.

Studies now suggest that the severity of sickle cell disease can be reduced by using drugs that stimulate production of HbF. Even increases as modest as 4% may have significant benefits for these patients.

Hydroxyurea. Hydroxyurea (Droxia, Hydrea) destroys cells in the bone marrow, which results in an increase in special cells that can produce HbF. It is currently the only drug in general use to prevent acute sickle cell crises.

Hydroxyurea is used to treat adults and adolescents with moderate-to-severe recurrent pain (occurring three or more times a year). Hydroxyurea reduces sickling crises and pain, priapism, the number of transfusions, and life-threatening complications in this group. The benefits appear to be long-lasting. Hydroxyurea is not a cure-all. Not all patients respond to hydroxyurea, and the best candidates for the treatment are not yet clear. Small studies have reported no protection from damage in the spleen or bones and joints. Effects on stroke and complications in the eye or kidney are not yet known.

Hydroxyurea is still being investigated in young people. To date, the response to the drug in children and teenagers with sickle cell disease is similar to the response in adults, and few severe adverse effects are being reported. Recent research also suggests that hydroxyurea is safe and beneficial for infants. A 2005 study indicated that long-term hydroxyurea treatment can improve height, weight, and spleen function, and reduce episodes of acute chest syndrome. Patients in the study started the treatment as babies, and most patients took the drug for at least 4 years. The drug was given by mouth in a flavored liquid form.

Side effects include gastrointestinal problems, headache, drowsiness, and skin and nail changes. In rare cases, there have been reports of hallucinations and seizures. The drug may also cause leg ulcers and gangrene in some patients. Patients should handle hydroxyurea with care and wash their hands before and after touching the bottle or capsules. Household members who are not taking hydroxyurea (such as caregivers) should wear disposable gloves when handling the medicine or its bottle.

Cytidine Analogues. Cytidine analogues increase HbF production by affecting the genes that regulate it. Decitabine is one such drug that was developed to treat leukemia and other blood malignancies. Early studies are suggesting that it significantly increases HbF production, even in patients in whom treatment with hydroxyurea failed. Only minor toxic side effects have been reported to date.

Butyrates. Butyrates are natural fatty acids, the end-products of fermented carbohydrates in the intestinal tract that are also metabolized from fiber. One derivative, arginine butyrate, has been under investigation for some time in sickle cell for its role in stimulating production of HbF. Because its actions are different from hydroxyurea, experts hope the two drugs may eventually be used in combination. However, arginine butyrate is difficult to administer, and different forms that might make it simpler to use are needed.

General Guidelines for Managing a Sickle Cell Crisis. The basic objectives for managing a sickle cell crisis are control of pain and rehydration by administration of fluids. Oxygen is typically given for acute chest syndrome. Effective pain medications are available to help reduce the severe pain of sickle cell crises.

Accurate and continually updated assessment of pain determined by patient input and participation is at the crux of effective care for children with sickle cell disease. Often, however, patients are not given the treatment they require.

• Many patients, their families, and even doctors are hesitant to use opioids aggressively because of fear of addiction. This fear, however, is nearly always unwarranted. Addiction occurs in only about 1 - 3% of patients with sickle cell disease who are taking opioids.
• Many patients use emergency rooms of large hospitals for treating acute pain. Waiting times are long, and there is no single health care provider who knows the patient and can offer consistent assessment and management of pain.
• Many doctors do not understand the nature of sickle cell pain. For example, early phases of sickle cell crisis can cause severe pain before test results confirm a diagnosis of a crisis. In such cases, health professionals may question the patient's self-reporting and withhold appropriate pain medication.
• Patients may behave normally (talking on the phone, sleeping) and not appear to be in pain, but have actually developed coping behaviors to allow them to function in spite of severe pain.
• Children and adults report pain differently, with children tending to report less pain than they actually feel. (One way of determining the severity of pain that a child feels is to show pictures of faces demonstrating degrees of pain and asking the child to point to the one that best expresses his or her experience.)

Adult patients and parents of children with the disease should insist on aggressive pain-relief treatment. If doctors show any reluctance to administer medications after the onset of pain, patients or caregivers should not hesitate to seek a more responsive health care professional.

All patients should have a treatment plan that helps guide them and their families during a pain episode. Plans should outline which medicines to take and when to seek medical help. Patients and families should learn to recognize symptoms early and begin managing with an appropriate amount of pain medication.

Opioids. Severe pain should be treated with strong painkillers, usually opioids. Opioids are generally given orally to adults and adolescents and intravenously to children. Nevertheless, there are exceptions. Studies indicate that oral medications are also effective in children.

• Morphine is often used for frequent or prolonged episodes of pain. Unfortunately, its effectiveness is not as long-lasting in sickle cell patients as it is in other patients with severe pain, such as those with cancer.
• The opioid meperidine (Demerol) is also used for sickle cell crises. Meperidine is not as powerful as morphine, however, and, if used for prolonged periods, may cause twitches, tremors, and disturbed mental states including seizures.
• Some newer synthetic opioids such as fentanyl (Duragesic) or hydromorphone(Dilaudid) have a rapid onset and possibly fewer side effects than morphine. Fentanyl can be applied using a patch, which may help some patients who have difficult receiving intravenous drugs. It takes 12 hours to be effective, however.
• Oral drugs, such as methadone, oral morphine, codeine, and oxycodone, are useful for home management of chronic pain and for transitional treatments between the hospital and home. Tramadol (Ultram) is a potent oral painkiller that has opioid-like properties but is not as addictive. (Dependence and abuse have been reported, however.) It may be very useful for sickle cell patients who need painkillers outside the hospital. It has minimal effects on respiratory function and has a low potential for addiction.

Possible side effects of opioids are vomiting and nausea, itching, constipation, itching, skin rashes, and problems urinating. If the patient vomits or becomes nauseated, the doctor may prescribe prochlorperazine (Compazine). Devices have been developed to allow patients to administer their own painkillers as needed.

Anti-Inflammatory Drugs. Because of the potentially serious side effects of opioids, doctors are constantly searching for safer and easier ways of reducing the severity of pain of sickle cell crises. Because experts believe that inflammation is a major contributor to the pain of sickle cell disease, drugs that reduce inflammation are being studied:

• Prescription-strength NSAIDs include diflunisal (Dolobid) and ketorolac (Toradol). Ketorolac may be particularly helpful in relieving bone pain, and may be effective for individuals who cannot tolerate opioids. In one study, it was superior to meperidine and had fewer side effects. Studies have suggested, however, that when used as first-line therapy in an acute crisis, ketorolac is effective only in about half of episodes.
• Corticosteroids are powerful anti-inflammatory drugs that are commonly used to treat pain caused by inflamed muscles and joints. Such drugs include methylprednisolone (Medrol) and dexamethasone (Decadron, Hexadrol). Studies suggest that using these drugs along with opioids may help some sickle cell patients. Because steroids can suppress the body's infection fighters, they should not be given to patients with bacterial infections or any serious medical complication.

Epidural Anesthesia. An epidural analgesia (injection of an anesthetic into the spinal fluid) may be very effective for pain that is unresponsive to the usual therapies.

Initial Management. Acute chest syndrome can be fatal and must be treated immediately. Basic treatments include the following:

• Supplementary oxygen -- this is critical and life saving.
• Administration of fluids -- overhydration should be avoided to reduce the risk of fluid in the lungs.
• Pain relievers
• Bronchoscopy (a diagnostic procedure involving insertion of a tube into the lower airways) may be needed to identify infection.

Other Treatments. Other treatments include:

• High-dose intravenous corticosteroids (usually dexamethasone) may hasten recovery from acute chest syndrome and reduce the duration of hospitalization. They are also important if fat embolisms develop.
• Antibiotics that specifically target the organisms ( Chlamydia, Mycoplasma) that commonly trigger acute chest syndrome. Such antibiotics include erythromycin, azithromycin, clarithromycin, and various tetracyclines.
• Transfusions are important early on for rapid improvement in severe cases, especially if fat embolisms have developed.

To increase oxygen levels in children hospitalized for acute chest syndrome, a simple breathing technique known as incentive spirometry may also be beneficial. A spirometer is a hand-held plastic device commonly used by asthma patients to measure their lung capacity and by patients after surgery to increase intake of oxygen. Patients with sickle cell disease are asked to inhale and exhale into this device every 2 hours during the day and when wake at night until their chest pain subsided. This device forces more air into the lungs, and may help prevent the serious drop in oxygen levels and the risk for infection caused by acute chest syndrome. Spirometry leads to slower rates of collapsed lung tissue and infections. This very inexpensive and simple treatment might have beneficial long-term effects.

General Approach to Treating Infections. Fever in any sickle cell patient should be considered an indication of infection. Temperatures over 101°F in children warrant a call to the doctor. Adults with sickle cell should call the doctor if they have a have fever over 100°F and any signs of infection, including chest pain, productive cough, urinary problems, or any other symptoms. Some approaches for treating infections include:

• Hospitalization for infections. When sickle cell patients develop infections, they are nearly always hospitalized immediately and treated with intravenous or high-dose injections of antibiotics in order to prevent septicemia, the dangerous spread of the infection throughout the body. Antibiotics called cephalosporins [cefotaxime (Claforan), ceftriaxone (Rocephin), or cefuroxime (Ceftin)] are typically used. Repeated hospitalizations are very disruptive for both children and adults. Studies have found that older children whose fever is below 38.5°C (101°F) and who have no serious infection or other complications may not need hospitalization. Children who have indications of serious complications of infection (higher fevers, pain, a history of pneumonia, and signs of dehydration) should remain in the hospital.
• Treatment of osteomyelitis. If osteomyelitis, an infection in the bone, occurs, a 6-week antibiotic course is needed, most of it intravenous. An accurate diagnosis of osteomyelitis is sometimes difficult to make, because bone damage from sickling can cause similar symptoms. It should be strongly considered in children with signs of pain and swelling in the legs, a high white blood cell count, high fever, and high levels of a test that measures so-called sedimentation rates. It is important, however, to confirm the presence of an actual infection before administering antibiotics, because the antibiotic treatment required for osteomyelitis is so intensive and prolonged. The most common cause of osteomyelitis in children is Salmonella.
• Treatment of urinary tract infections. Urinary tract infections may be difficult to manage and can be a serious problem for pregnant women with sickle cell disease. Doctors should take a urine culture before beginning antibiotic treatment and another culture 1 - 2 weeks after treatment to be sure the infection has cleared up.

Bosentan (an endothelin receptor antagonist) and other drugs are used to treat this condition. Investigational therapies include nitric oxide, L-arginine (which converts to nitric oxide), blood transfusions, warfarin, vasodilators, and sildenafil (Viagra). Hydroxyurea does not appear to help.

Folic acid and possibly iron supplements are often given to help treat the anemia that occurs in patients with sickle cell disease. (Patients who are given multiple transfusions may experience iron overload, and iron supplements should be avoided in such cases. Also, folic acid can mask pernicious anemia, which is caused by deficiency of vitamin B12 and is more common in African-Americans than other populations.)

Kidney damage in patients with sickle cell disease can cause bleeding into the urine. Mild episodes can usually be treated with bed rest and fluids. Severe bleeding may require transfusions. ACE inhibitors are drugs commonly used to control high blood pressure and are proving to be important for preventing hypertension and kidney failure in sickle cell patients. Such drugs include captopril (Capoten), enalapril (Vasotec), quinapril (Accupril), benazepril (Lotensin), and lisinopril (Prinivil, Zestril).

Priapism causes prolonged and painful erections that can last from several hours to days. It is best to relieve this problem within 12 hours. Relief within 36 hours is important to avoid permanent impotence. Pain relief and intravenous fluids are the initial steps. Exchange transfusions may be used to reduce the hemoglobin S and sickling that cause this condition. Drugs used to prevent priapism include terbutaline and phenylephrine, which help restrict blood flow to the penis. Hormonal treatments such as leuprolide (Lupron) and diethylstilbestrol may prevent repetitive and prolonged episodes of priapism in severely affected teenage boys with sickle cell disease. A surgical procedure that implants a shunt to redirect blood flow is sometimes performed. Inflatable penile implants may help maintain potency without causing priapism. Researchers are also investigating other treatments including inhaled nitric oxide, arginine, and sildenafil (Viagra).

The spleen is often removed (splenectomy) in children who have one or two acute splenic sequestration crises. Transfusion therapy is an alternative for preventing acute splenic sequestration in high-risk patients. At this time there are no studies comparing overall survival and benefits between the two approaches.

Leg ulcers are difficult to treat. Simple treatment with a moist dressing usually provides the best results. To treat mild ulcers, the leg should be gently washed with cotton gauze soaked in mild soap or a solution of one tablespoon of household bleach to one gallon of water. A dressing soaked in diluted white vinegar may be applied every 3 - 4 hours.

More severe ulcers require debridement, which is the removal of injured tissue until only healthy tissue remains. Debridement may be accomplished using chemical (enzymes), surgical, or mechanical (irrigation) means. Hydrogels (Nu-Gel, Intrasite Gel, Scherisorb, Clearsite, Duoderm, Geliperm) are helpful in healing ulcers and are noninvasive and soothing. Topical antibiotics, saline or zinc oxide dressings, or cocoa butter or oil are also used depending on severity. The leg should be elevated. Bed rest for a week or more is sometimes required for severe ulcers.

Skin grafts and transfusions have been helpful in some extreme cases. In one promising study administering arginine butyrate for many weeks improved ulcer healing by 10-fold. (This drug is also under investigation for other beneficial effects in patients with sickle cell disease.)

Women who are pregnant should be treated at a high-risk clinic. They should take folic acid in addition to multivitamins and iron. Standard treatment is given for sickle cell crises, which may occur more frequently during pregnancy. The benefits of transfusions to prevent crises during pregnancy are not yet clear and experts recommend them only for women who experience frequent complications during pregnancy.

Women with sickle cell disease should talk to their doctors before becoming pregnant. Sexually active women should use contraception at all times.

At this time, the only true cure for sickle cell disease is bone marrow or stem cell transplantation. The bone marrow nurtures stem cells, which are early cells that mature into red and white blood cells and platelets. By destroying the sickle cell patient's diseased bone marrow and stem cells and transplanting healthy bone marrow from a genetically-matched donor, normal hemoglobin may be produced. Clinical studies using a few carefully selected patients have reported very successful results.

Up to 80 - 85% of patients who meet criteria for receiving a transplant receive remain disease free. Unfortunately, only about 7% meet the criteria for transplantation, including those who:

• Are age 16 or younger (generally considered the better candidates, but patients in their 20s have had successful transplants)
• Have severe symptoms but no long-term organ or neurologic damage
• Have a genetically matched brother or sister who will donate their marrow

Complications. Bone marrow transplant carries its own dangers and limitations. About 10% of those who have bone marrow transplants die from the treatment. Some complications include:

• In patients who do not receive a bone marrow donation from a matched sibling, the transplanted cells from a donor (called allogeneic grafts) may attack the patient's own tissues, a potentially fatal condition called graft-versus-host disease (GVHD). Drugs that destroy bone marrow and suppress immunity must be administered before the procedure so that the body's immune system does not attack the transplanted tissue. Still, this does not always prevent the problem.
• Other very serious complications include bleeding, pneumonia, and severe infection.
• Those who live but are not cured face long-term problems caused by the drugs used in transplantation and by the disease itself.
• Even in those who are cured, long-term consequences may include a higher risk for cancer and infertility.

The use of umbilical cord blood and cells from placentas is showing promise for providing healthy stem cells to patients who do not have genetically matched donors for bone marrow transplant. Cord blood has certain advantages over stem cell transplantation, including the capacity to produce more cells quickly. Because immune factors in cord blood are immature, the risk and severity of graft-versus-host disease may be reduced.

Early clinical trials are also reporting some success with a process called partial chimerism, in which a mixture of the patient's and a donor's bone marrow is used. The procedure has far fewer side effects because all the bone marrow is not destroyed. Although some sickle blood cells remain, small studies indicate that the patients are still free of the typical infections and pain of the disease.

Transfusions are often critical for treating sickle cell disease. In some cases, they may be given on a regular basis to prevent stroke or other life-threatening complications of the disease. Ongoing transfusions can reduce episodes of pain and acute chest syndrome. They can also help improve height and weight in children with sickle cell disease. Regular transfusions, however, can have severe side effects. Normal hemoglobin levels for patients with sickle cell disease are around 8 g/dL. Doctors will try to keep the hemoglobin level no higher than 10 g/DL after transfusion.

Transfusions may be required by sickle cell patients either for specific episodes (used only for specific events) or as chronic transfusions (ongoing transfusions).

Episodic Transfusions. Episodic transfusions are needed in the following situations:

• To manage sudden severe events, including acute chest syndrome, stroke, widespread infection (septicemia), and multi-organ failure.
• To manage severe anemia, usually caused by splenic sequestration (dangerously enlarged spleen) or aplasia (halting of red blood cell production, most often caused by parvovirus). Transfusions are generally not required for mild or moderate anemia.
• Before major surgeries. Some evidence suggests that a conservative transfusion regime is as effective as aggressive transfusions in these cases, but more research is needed. Transfusions are generally not required for minor surgeries.

Chronic Transfusions. Chronic (on-going) transfusions are used for:

• Stroke Prevention. Chronic transfusions are also used to prevent first or recurrent strokes. Evidence shows that regular (every 3 - 4 weeks) blood transfusions can reduce the risk of a first stroke by 90% in high-risk children. The objective of such transfusions is to reduce hemoglobin S concentrations to less than 30% of total hemoglobin. In addition, studies indicate that as many as 90% of patients who have experienced a stroke do not experience another stroke after 5 years of transfusions. In 2004, the National Heart, Lung, and Blood Institute (NHLBI) issued a clinical alert strongly advising doctors against terminating regular transfusions for high-risk children.
• Pulmonary hypertension and chronic lung disease
• Heart failure
• Chronic kidney failure and severe anemia
• Unusually severe and protracted episodes of pain

Chronic blood transfusions carry their own risks, including iron overload, alloimmunization (an immune response reaction), and exposure to bloodborne pathogens. Still, data from large-scale trials suggest that the risks for stroke outweigh the risks associated with transfusions. Researchers are working on ways to reduce the side effects associated with transfusion treatment.

Kinds of Transfusions. Transfusions may be either simple or exchange.

• Simple Transfusion. Simple transfusions involve the infusion of one or two units of donor blood to restore blood volume levels and oxygen flow. It is used for moderately severe anemia, severe fatigue, and nonemergency situations when there is a need for increased oxygen. It is also used for acute chest syndrome.
• Exchange Transfusion. Exchange transfusion involves drawing out the patient's blood while exchanging it for donor red blood cells. It can be done as manual procedure or as automatic one called erythrocytapheresis. Exchange transfusions should be used promptly if there is any evidence that the patient's condition is deteriorating. It prevents stroke and also may be used in patients with severe acute chest syndrome and to reduce the risk of iron overload in patients who require chronic transfusion therapy. Studies suggest that it may improve oxygenation and reduce hemoglobin S levels. Exchange transfusion may also reduce the risk of heart failure and help prevent fat embolism, a life-threatening condition in which fatty tissue from the bone marrow travels to blood vessels in the lungs and cuts off oxygen.

Iron Overload and Chelation Therapy. Iron overload increases risk for complications, including liver cancer and heart failure. A liver biopsy accurately determines whether excess iron levels are present. A non-invasive test called a superconducting quantum interference device (SQUID) should be used if available.

Chelation therapy is used to remove excess iron stores in the body that can harm the liver, heart, and other organs. The drug deferoxamine (Desferal) is commonly used during such therapy. Unfortunately, deferoxamine has some severe side effects and must be used with a pump for about 12 hours each day. Many patients do not continue treatment. In 2005, the drug deferasirox (Exjade) was approved for the treatment of transfusion-related iron overload in patients ages 2 and older. It is taken once a day by mouth. Patients mix the pills in liquid and drink the mixture. This new treatment may make chelation therapy much easier and less painful for patients.

Other Complications of Transfusion Therapy.

• Immune reactions. An immune reaction may occur in response to donor blood. In such cases, the patient develops antibodies that target and destroy the transfused cells. This reaction, which can occur 5 - 20 days after transfusion, can result in severe anemia and may be life-threatening in some cases. It can be generally prevented with careful screening and matching of donor blood groups before the transfusion.
• Hyperviscosity. With this condition, a mixture of hemoglobin S and normal hemoglobin causes the blood to become sticky. The patient is at risk for high blood pressure, altered mental status, and seizures. Careful monitoring can prevent this condition.
• Transmission of viral illness. Before widespread blood screening, transfusions were highly associated with a risk for hepatitis and HIV. This complication has decreased considerably.

Nitric oxide, a soluble gas, is a natural chemical in the body that relaxes smooth muscles and expands blood vessels. Hemoglobin removes nitric oxide. Because sickle cells release hemoglobin, patients with the disease are deficient in nitric oxide. This lack of nitric oxide constricts blood vessels and causes pain in sickle cell diseases. In adult patients, men may be more susceptible to this effect than women. Some studies indicate that inhaling nitric oxide may slow the disease process and improve symptoms in acute sickle cell crises. It is difficult to administer, however. More studies are needed. (Nitric oxide is not the same substance as nitrous oxide, the so-called laughing gas used in dentistry.)

Sickle cell disease can cause red blood cells to break apart. This process is called hemolysis. Hemolysis causes a lack of the amino acid arginine. Arginine is involved in producing nitric oxide. Recent research suggests that a lack of arginine may contribute to the development of pulmonary hypertension, a leading cause of death in patients with sickle cell disease. Pulmonary hypertension causes high blood pressure in the arteries that carry blood to the lungs.

A 2005 study found that patients with sickle cell who had low levels of arginine were 3.6 times more likely to die than patients with high arginine levels. Most patients in the study died from pulmonary hypertension. Scientists are working on developing a blood test that could measure amino acid levels and help identify patients at greatest risk of death. They are also working on developing drugs that could block arginase, a protein in cells that is released during hemolysis, which consumes arginine. There is no evidence indicating that arginine nutritional supplements are helpful or harmful for patients with sickle cell disease. Patients should talk to their doctor before taking these or other supplements.

Researchers are studying the mechanisms behind cell membrane damage, dehydration, and potassium loss in order to develop drugs that will inhibit these processes. Drugs under investigation include those that specifically block the Gardos channel, which is an important route for potassium loss and dehydration. Researchers are also studying specific types of mineral supplements, such as magnesium pidolate and zinc sulfate. Initial studies have shown promising results for zinc’s efficacy in preventing red blood cell dehydration, but more research is needed.

Prevention and Lifestyle Changes

No o proven methods prevent either sickle cell crises or long-term complications of sickle cell disease. By taking precautions and aggressively managing problems that occur, however, patients are now living longer, with a better quality of life.

To prevent or reduce the severity of long-term complications, a number of precautions may be helpful:

• Have regular physical examinations every 3 - 6 months.
• Have periodic and careful eye examinations.
• Have sufficient rest, warmth, and increased fluid intake. (These are critical precautions for reducing oxygen loss and the risk for dehydration.)
• Avoid conditions, such as crowds, that increase risk for infections.
• Avoid excessive demands on the body that would increase oxygen needs (physical overexertion, stress). Low impact exercise (leg lifts, light weights) may be useful and safe for maintaining strength, particularly in the legs and hips, but patients should consult their doctor about any exercise program.
• Avoid high altitudes if possible. If flying is necessary, be sure that the airline can provide oxygen.
• Do not smoke, and avoid exposure to second-hand smoke. Both active and passive smoking may promote acute chest syndrome in patients with sickle cell disease.

Vaccinations. Everyone with sickle cell disease should have complete regular immunizations against all common infections. Children should have all routine childhood vaccinations. The following are important vaccinations for everyone with sickle cell disease:

• Pneumococcal vaccines. All sickle cell patients should be vaccinated with the pneumococcal vaccine. There are two types of pneumococcal vaccines; the choice between them depends on the age of the patient. Infants and children less than 2 years of age should receive 4 doses of the pneumococcal conjugated vaccine (Prevnar) between 2 - 15 months of age. (This vaccine has helped reduce the rate of serious pneumococcal disease by more than 90%.) The pneumococcal polysaccharide vaccine should be administered at age 2 years or older, repeated after 3 - 5 years for patients younger than age 10, or in 5 years for patients older than age 10.
• Vaccination against Haemophilus influenza, the major cause of childhood meningitis, starting at age 2 months.
• Influenza vaccines should be given every winter, starting at age 6 months.
• Meningococcal vaccination for patients age 5 and older.
• Hepatitis B vaccine. Anyone starting transfusion therapy should receive this vaccine.

Tuberculosis skin testing should be performed every year.

Antibiotics. In addition to regular immunizations, preventive (prophylactic) antibiotics are the best approach for protection against pneumonia and other serious infections among children with sickle cell disease. Babies diagnosed with sickle cell are given daily antibiotics, starting at 2 months of age and continuing through 5 years of age. Penicillin is usually the antibiotic given, unless a child is allergic to it.

Many patients stop taking their antibiotics or the parents stop giving them to their children. Doctors are concerned about developing bacterial resistance to common antibiotics and researchers warn that patients might experience breakthrough infections as resistance becomes more frequent.

Foods. Good nutrition, while essential for anyone, is critical for patients with sickle cell disease. Some dietary recommendations include:

• Fluids are number one in importance. The patient should drink as much water as possible each day to prevent dehydration.
• Diet should provide adequate calories, protein, fats, and vitamins and minerals. Patients and families should discuss vitamin and mineral supplements with their doctors and nurses.
• Studies on omega-three fatty acids, found in fish and soybean oil, suggest that they might make red blood cell membranes less fragile, and possibly less likely to sickle, although no studies have proven this definitively. Fish and soy products have health benefits in any case. In one small study, fish oil supplements reduced the frequency of painful episodes over the course of a year.

Vitamins. Patients should take daily folic acid and vitamin B12 and B6 supplements. Vitamin B6 may have specific anti-sickling properties. Some experts recommend 1 mg folic acid, 6 microgram vitamin B12, and 6 mg vitamin B6. Foods containing one or all of these vitamins include meats, oily fish, poultry, whole grains, dried fortified cereals, soybeans, avocados, baked potatoes with skins, watermelon, plantains, bananas, peanuts, and brewer's yeast. Of note, folic acid can mask pernicious anemia, which is caused by deficiency of vitamin B12 and is more common in African-Americans than other populations.

Click the icon to see an image of vitamin B6 sources.

Note on Iron. Although sickle cell disease is often referred to as anemia, patients should avoid iron supplements or iron rich foods when receiving multiple transfusions, which increase the risk for iron-overload.

In assessing the seriousness of this disease, no one should underestimate its emotional and social impact. For the family, nothing is more heartbreaking than watching their child endure extreme pain and life-threatening medical conditions. The patient endures not only the pain itself but also the emotional strain from unpredictable bouts of pain, fear of death, and lost time and social isolation at school and work. Academic grades among patients average less than C, even in children with a low frequency of hospitalization (averaging 17 days a year).

These problems continue over the years, and both children and adults with sickle cell disease often suffer from depression. The financial costs of medical treatments combined with lost work can be very burdensome.

Any chronic illness places stress on the patient and family, but sickle cell patients and caregivers often face great obstacles in finding psychological support for the disease. Communities in which many sickle cell patients live generally lack services that can meet their needs, and professionals who work in their medical facilities are often overworked. In a study comparing patients with different kinds of long-term illnesses, those with sickle cell disease gave the lowest scores to their doctors and other professional caregivers for compassion, and were least satisfied with their medical care.

It is very important for patients and their caregivers to find emotional and psychological support. No one should or can endure this life-long disease alone. Unfortunately, studies indicate that most patients do not receive even basic supportive care that could help reduce the anxiety and intensity of pain that occurs when a sickle cell crisis erupts.

The following are some measures that some people find helpful in dealing with this disease:

• Stress Reduction. Stress reduction techniques and relaxation methods appear to be helpful. Breathing and mediation techniques may be very helpful.
• Cognitive-Behavioral Therapy. Studies suggest that cognitive behavioral therapies that teach coping skills can result in less negative thinking and even less pain. Coping skills refer to the patient's ability to respond to symptoms, such as pain.
• On-Line Support Help. Computer on-line services are now valuable sources of support groups and access to research. They are particularly valuable for patients who cannot easily leave home or for patients who are ill.
• Support Associations. Parent and professional support associations still offer the best and least expensive sources of help.

Other important factors are those that help maintain positive attitudes including spirituality, humor, or having important life goals (such as having children or pursuing a career).

Resources

• www.sicklecelldisease.org -- Sickle Cell Disease Association of America
• www.nhlbi.nih.gov -- National Heart, Lung, and Blood Institute (NHLBI)
• www.scinfo.org -- Sickle Cell Information Center
• www.sicklecellsociety.org -- Sickle Cell Society (UK)
• www.sicklecell-info.org -- NHLBI Comprehensive Sickle Cell Centers
• www.clinicaltrials.gov -- Find clinical trials

References

Adams RJ, Brambilla D; Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) Trial Investigators. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N Engl J Med. 2005 Dec 29;353(26):2769-78.

Al Hajeri AA, Fedorowicz Z, Omran A, Tadmouri GO. Piracetam for reducing the incidence of painful sickle cell disease crises. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD006111.

Bernaudin F, Socie G, Kuentz M, et al Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood. 2007 Oct 1;110(7):2749-56. Epub 2007 Jul 2.

Dunlop RJ, Bennett KC. Pain management for sickle cell disease. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD003350.

Fathallah H, Atweh GF. Induction of fetal hemoglobin in the treatment of sickle cell disease. Hematology Am Soc Hematol Educ Program. 2006:58-62.

Halasa NB, Shankar SM, Talbot TR, et al. Incidence of invasive pneumococcal disease among individuals with sickle cell disease before and after the introduction of the pneumococcal conjugate vaccine. Clin Infect Dis. 2007 Jun 1;44(11):1428-33. Epub 2007 Apr 18.

Hankins JS, Wynn LW, Brugnara C, Hillery CA, Li CS, Wang WC. Phase I study of magnesium pidolate in combination with hydroxycarbamide for children with sickle cell anemia. Br J Haematol. 2008 Jan;140(1):80-5. Epub 2007 Nov 7.

Lee MT, Piomelli S, Granger S, et al. Stroke Prevention Trial in Sickle Cell Anemia (STOP): extended follow-up and final results. Blood. 2006 Aug 1;108(3):847-52.

Mehta SR, Afenyi-Annan A, Byrns PJ, Lottenberg R. Opportunities to improve outcomes in sickle cell disease. Am Fam Physician. 2006 Jul 15;74(2):303-10.

Singh PC, Ballas SK. Drugs for preventing red blood cell dehydration in people with sickle cell disease. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003426.

Tanabe P, Myers R, Zosel A, et al. Emergency department management of acute pain episodes in sickle cell disease. Acad Emerg Med. 2007 May;14(5):419-25. Epub 2007 Mar 26.

U.S. Preventive Services Task Force. Screening for Sickle Cell Disease in Newborns: U.S. Preventive Services Task Force Recommendation Statement. AHRQ Publication No. 07-05104-EF-2, September 2007. Agency for Healthcare Research and Quality, Rockville, MD.

Review Date:
3/11/2008
Reviewed By:
A.D.A.M. Editorial Team: David Zieve, MD, MHA, Greg Juhn, MTPW, David R. Eltz, Kelli A. Stacy, ELS. Previously reviewed by Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital (1/1/2008).

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