Sickle Cell Disease - Complications

Using Antibiotics for Prevention. Preventive (prophylactic) antibiotics are the best approach for protection against pneumonia and other serious infections among children with sickle cell disease. Children diagnosed with sickle cell are given daily antibiotics, usually penicillin, unless a child is allergic and then alternatives are available. The ideal age for stopping preventive antibiotics is not yet clear, although the risk for serious infections are relatively lower in children older than 5 years of age.

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Unfortunately, studies suggest that children who are on public medical insurance often receive inadequate treatment. In addition, many patients stop taking their antibiotics or the parents stop giving them to their children. Doctors are also concerned about developing bacterial resistance to common antibiotics and researchers warn that patients might experience breakthrough infections as resistance becomes more frequent.

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 for everyone with sickle cell disease:

Vaccination against Haemophilus influenza, the major cause of childhood meningitis.
Flu (influenza)vaccines should be received every winter.
Pneumococcal vaccine. All sickle cell patients should be vaccinated with the pneumococcal vaccine. Protection lasts for over6 years in most people. Children with sickle cell disease should receive3 doses of the pneumococcal conjugated vaccine (Prevnar) between 2 and6 months of age, followed by2 doses at age1 and then vaccinations at age two, 5, and every 10 years afterward. (Some experts recommend every5 years rather than every 10 years.)
Tuberculosis test every year.
Hepatitis B vaccine. Anyone starting transfusion therapy should receive this vaccine if they had not been immunized as children.

Other Effects on the Lungs

Impaired Lung Function. A 2003 study observed impaired lung function starting at very early ages (5 years and older) in children with sickle cell. Although not outside the normal range, such signs of abnormalities in the airways of the lungs may warrant early treatments for obstructive or restrictive lung disease (which are similar to those for asthma patients).

Pulmonary Hypertension.Pulmonary hypertension is a serious condition that develops if blood pressure in the lungs increases, in some cases to a dangerous level. Research published in 2004 in the New England Journal of Medicine confirmed that it is an important and often unrecognized complication and cause of death in sickle cell disease. Based on the evidence, the researchers urged that all adults with sickle cell disease undergo echocardiographic testing to identify and treat those patients at highest risk. The primary symptom 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. Bosentan (an endothelin receptor antagonist), and other drugs are used to treat this condition. Investigative therapies include nitric oxide, L-arginine (which converts to nitric oxide), blood transfusions, warfarin, vasodilators, and sildenafil (Viagra). Hydroxyurea does not appear to be effective for treating sickle cell associated pulmonary hypertension.

Click the icon to see an image of cor pulmonale.

Stroke

After acute chest syndrome, stroke is the most common killer of patients with sickle cell disease who are older than3 years old. Between 8 - 10% of patients suffer strokes, typically at about age 7. Transfusions are proving to prevent a first stroke as well as recurrence. Strokes are usually caused by blockages of vessels carrying oxygen to the brain.Patients with sickle cell diseaseare 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 can be treated surgically. (Some experts believe that any patient who has neurologic symptoms indicating a potential stroke should undergo angiography, an invasive diagnostic technique useful for detecting aneurysms.)

Click the icon to see an image of stroke.

Transfusions for Prevention of Stroke. Compelling data show that regular (every 3 to 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. 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 December 2004, the National Heart, Lung, and Blood Institute (NHLBI) issued a clinical alert strongly advising doctors against terminating regular transfusions for high-risk children. The alert was based on data from the Stroke Prevention Trial II (STOP II) that was presented at the the American Society of Hematology annual conference. STOP II assessed if children with sickle cell anemia who were at high risk for stroke could safely stop receiving preventive blood transfusions after a minimum of 30 months. The trial was halted early due to compelling evidence that transfusion cessation significantly increased the risk for stroke.

Chronic blood transfusions carry their own risks including iron overload, alloimmunization (an immune response reaction), and exposure to bloodborne pathogens. Still, the STOP II trial data 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.

Unfortunately, no tests can definitely determine which individual children are at highest risk for a first stroke and, therefore, would be candidates for ongoing 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, the results of the STOP II trial indicated that high-risk children were 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. A 2001 study indicated that giving transfusion therapy to children who showed abnormalities after an MRI reduced the risk for stroke.
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.

Until diagnostic tests can be more precise, or effective alternative treatments to transfusions exist, patients and their caregivers and doctors must make the best decisions they can.

Anticoagulants. Researchers have investigated anti-blood clotting drugs such as aspirin and heparin for preventing stroke. However, their use is controversial, and their effects on children are unclear and understudied.

Anemia

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

Hemolytic Anemia and Aplastic Crises. Because of the short life span 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. Episodes of hemolytic anemic are called aplastic crises, which are usually managed well with transfusions. In about 80% of cases, aplastic crises are triggered by a virus called human parvovirus B19. There is some evidence that the virus increases the risk for neurologic complications, including encephalitis and stroke. (This virus is common and usually harmless in healthy individuals.)

Chronic 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. 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 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.)

Problems in the Kidney

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.

Click the icon to see an image of kidney anatomy.

Treatment for Kidney Problems. Kidney damage in sickle cell patients 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), quinipril (Accupril), benazepril (Lotensin), and lisinopril (Prinivil, Zestril).

Problems in the Genital Tract

A reported 38 - 42% of males, including children, with sickle cell disease suffer from priapism. Priaprism causes prolonged and painful erections. 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.

Treatment for Priapism. Priapism, prolonged and sometimes painful erections, must be treated to prevent partial or complete impotence, which can result from erections that last several hours to days. 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 asleuprolide (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).

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

Problems in the Liver

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.

Click the icon to see an image of cor pulmonale.

Gallbladder Disease

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.

Treatment of Gallbladder Disease. Children with sickle cell disease have an increased risk for gallstones. However, if they have no symptoms, no treatment is usually necessary. If the have recurrent or severe pain from gallstones, the gallbladder may need to be removed. Minimally invasive procedures (using laparoscopy) reduce possible complications. [See In-Depth Report #10: Gallstones.]

Click the icon to see an image of cholithiasis.

Damaged Spleen

The spleen of most adults with sickle cell anemia is nonfunctional due to recurrent episodes of oxygen deprivation that eventually destroys it. Injury to spleen causes abnormalities 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 enlarged from trapped blood.

Treatment for Complications in the Spleen. 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.

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

Problems in the Bones and Joints

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. Ultrasound is also a helpful tool in diagnosing and treating these abnormalities.

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

Leg Sores and Ulcers

Leg sores and ulcers occur in up to 10% of sickle cell patients and usually affect patients older than 10 years. They are difficult to treat, and, at this time, simple treatment with a moist dressing 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 three to four 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 (e.g. 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 and 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 a promising 2002 study administering arginine butyrate for many weeks improved ulcer healing by ten-fold. (This drug is also under investigation for other beneficial effects in sickle cell patients.)

Neurological Complications

In one 2000 study of adults with sickle cell disease, 22% suffered from neurologic complications. Stroke is a major factor in such problems. Sickle cell disease also poses a high risk for mild mental deficiency from low levels of oxygen in brain tissue or from silent strokes, even in the absence of a major stroke. Such deficiencies can impair learning and behavior but may not even show up on normal imaging tests and thus may not be attributed to sickle cell disease. Some experts recommend clinical trials using brain scans to detect the location of small injuries and try to determine whether they might be causing mental or behavioral problems that are inaccurately believed to be unrelated to the disease.

Pregnancy andSickle Cell Disease

Women with sickle cell disease who become pregnant are at higher risk for complications, but serious problems have dropped significantly over the past decades. A 2001 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 occur in nearly half of 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%.

Treatment During Pregnancy. 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.

Other Medical Complications

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.