Sickle cell disease is the most common single gene disorder in black Americans, affecting approximately one in 375 persons of African ancestry.1 Sickling conditions are also common in persons from Mediterranean countries, Turkey, the Arabian peninsula and the Indian subcontinent. Many Spanish-speaking persons in the United States, as well as people from the Caribbean and parts of South and Central America, are affected.
The first description of sickle cell disease, published in 1910,2 was followed by six decades of genetic, hematologic, pathologic, clinical and molecular observations. Since the mid-1970s, two longitudinal prospective studies of children with sickle cell disease have produced a large body of clinical data on the evolution of the disease from birth.3,4 The U.S. study followed 3,500 patients with sickle cell disease through sickness and health.4 Therapeutic advances based on these longitudinal studies have improved longevity and quality of life in patients with sickle cell disease.
Variants of Sickle Cell Disease
The common variants of sickle cell disease are homozygous sickle cell disease (hemoglobin SS disease), doubly heterozygous sickle hemoglobin C disease (hemoglobin SC disease) and the sickle β-thalassemias.
In homozygous sickle cell disease, the child inherits a sickle (S) gene from each parent. In sickle hemoglobin C disease, the child inherits an S gene from one parent and a C gene from the other parent. In neither variant can normal hemoglobin (hemoglobin A) be produced.
In the sickle β-thalassemias, mutation of the βA gene results in a total inability to produce the normal βA globin chain (β0) or a reduction in its production (β+). The child with sickle β-thalassemia inherits an S gene from one parent and a β-thalassemia gene from the other parent.
If the child inherits an S gene from one parent and another abnormal hemoglobin, such as D, G or O, from the other parent, other rarer variants result.
The normal hemoglobin present in the child with sickle β+-thalassemia (less than 30 percent hemoglobin A) ameliorates the clinical picture. In general, this is the mildest variant of sickle cell disease, followed in severity by sickle hemoglobin C disease. Homozygous sickle cell disease and sickle β0-thalassemia have a comparable spectrum of severity, and specific laboratory studies are needed to distinguish between the two conditions (Table 1).
|Sickle cell variants||Hemoglobin electrophoresis (< 2 months of age)†||Serial complete blood count, reticulocyte count||Hematologic studies (9 months of age)||Parents' usual phenotypes∥|
|MCV‡||Hemoglobin A2 (%)§||Hemoglobin F (%)§||DNA dot blot||One parent||Other parent|
|Homozygous sickle cell disease, or hemoglobin SS disease||FS||Hemolysis and anemia usually by 6 to 12 months of age||Normal or increased||<3.6||< 25||βS||AS||AS|
|Sickle β0-thalassemia||FS||Hemolysis and anemia usually by 6 to 12 months of age||Decreased||>3.6||< 25||βAβS||AS||A on routine electrophoresis|
|A2 > 3.6 on quantitative electrophoresis|
|F increased on quantitative electrophoresis|
|MCV decreased on hemogram|
|Sickle β+-thalassemia||FSA||Mild anemia or no anemia by 2 years of age||Normal or decreased||>3.6||<25||βAβS||AS||A on routine electrophoresis|
|A2 > 3.6 on quantitative electrophoresis|
|MCV decreased on hemogram|
|Hemoglobin SC disease||FSC||Mild anemia or no anemia by 2 years of age||Normal or decreased||Not applicable||<15||βSβC||AS||AC|
Persons with sickle cell trait (the carrier form of this recessive condition) have more than 50 percent normal hemoglobin. They are essentially asymptomatic, except under unusual circumstances.
Sickle cell disease can be diagnosed in newborns, as well as older persons, by hemoglobin electrophoresis, isoelectric focusing, high-performance liquid chromatography or DNA analysis (Table 1). In general, these tests have comparable accuracy. The testing method should be selected on the basis of local availability and cost.
Solubility testing methods (Sickledex, Sick-lequik) and sickle cell preparations are inappropriate diagnostic techniques. Although these tests identify sickle hemoglobin, they miss hemoglobin C and other genetic variants. Furthermore, solubility testing is inaccurate in the newborn, in whom fetal hemoglobin is overwhelmingly predominant. Solubility testing methods also fail to detect sickle hemoglobin in persons with severe anemia.
Although hemolysis is a feature of all forms of sickle cell disease, patients with hemoglobin SC disease or sickle β+-thalassemia may not have significant anemia. Thalassemia is suspected if microcytosis or hypochromia is present in the absence of iron deficiency. A hematologist can assist in the often difficult task of determining the exact type of sickle cell disease, especially in the presence of rarer hemoglobin variants.
If both parents are accessible, studies of parental blood can aid in the diagnosis of sickle cell disease in the child. DNA analysis provides the most accurate diagnosis in patients of any age, but it is still relatively expensive.
In 41 states and the District of Columbia, newborns are now screened for sickle cell disorders. Screening programs were widely implemented after a double-blind, randomized, placebo-controlled trial demonstrated an 84 percent reduction in the incidence of pneumococcal sepsis, the most serious complication of sickle cell anemia in young infants, when prophylactic oral penicillin was initiated by the age of three months.5
A consensus development conference subsequently recommended universal nontargeted newborn screening to ensure that children with sickle cell disease were entered into a comprehensive system of care and received timely prophylactic penicillin.6 If the risk population in a state is too small to justify newborn screening economically, it is up to individual physicians to screen at-risk children who are in their care. Publications on newborn screening can be obtained from the Agency for Healthcare Research and Quality (formerly the Agency for Health Care Policy and Research) of the U.S. Department of Health and Human Services.7
Pathophysiology of Sickle Cell Disease
The symptoms of sickle cell disease stem from the peculiar properties of sickle hemoglobin and from hemolytic anemia.8–10 When deoxygenated, sickle hemoglobin forms rigid polymers that deform red cells, causing vaso-occlusion in the small vessels. Adherence of sickle cells to vascular endothelium results in intimal hyperplasia in larger vessels and causes slowed blood flow.11 The high white blood cell count found in most patients with sickle cell anemia results in the production of injurious cytokines.12
Individual patients may have other genetically controlled factors that increase thrombotic tendencies by mechanisms distinct from those that are due to sickle cells. In addition, known and unknown environmental factors can precipitate vaso-occlusion. Acidosis in muscle or body fluids, dehydration, cold temperatures and infections are known precipitants.
Patients with sickle cell disease can adapt to a hematocrit that is one half the normal value. However, if the anemia is severe, children develop coexistent cardiomegaly as a result of high blood flow. The increased cardiac workload, along with the extra hematopoiesis caused by the chronic hemolysis, raises the total calories required for growth.
Exacerbation of anemia by temporary bone marrow aplasia or splenic sequestration puts children with sickle cell disease at risk for life-threatening circulatory failure. In all infants, the spleen provides important protection against invading bacteria; it is also a source of opsonins and fixed-tissue macrophages, as well as antibody production. From the age of a few months on, children with sickle disease have increasing splenic dysfunction as the organ is at first intermittently and then chronically occluded with sickled cells.
In the child with sickle cell disease, health maintenance must include measures to prevent specific disease complications or at least to facilitate their diagnosis and ameliorate their impact (Table 2).
|Age||Routine visits||Laboratory tests||Immunizations||Medications||Screening procedures||Referrals||Anticipatory guidance|
|Prenatal or preconception visit||CBC with MCV and hemoglobin electrophoresis||Amniocentesis if needed||Geneticist High-risk obstetricsif needed||Genetic counseling|
|Birth to 6 months||Every 2 months||CBC every visit||Heptavalent conjugated pneumococcal vaccine at 2, 4 and 6 months||Penicillin V, 125 mg twice daily, initiated at 2 to 3 months of age||Hearing, vision, PPD as per standard practice||Genetic counseling of parents Review diagnosis and signs of illness.|
|6 months to 2 years||Every 3 months||UA annually|
CBC every 3 to 6 months
Ferritin or serum iron and TIBC once at 1 to 2 years of age
BUN, creatinine and LFTs once at 1 to 2 years of age
|Heptavalent conjugated pneumococcal vaccine booster at 15 months|
|Continue penicillin V.|
Start folic acid daily at 1 year of age.
|Hearing, vision, PPD as per standard practice||Consultation with sickle cell program or pediatric hematologist||Review signs of illness.|
Teach spleen palpation.
Discuss cold avoidance and maintenance of hydration as preventive measures.
|2 to 5 years||Every 6 months||CBC and UA at least yearly|
BUN, creatinine and LFTs every 1 to 2 years
|23-valent pneumococcal vaccine at 2 years of age; booster at 5 years of age|
Influenza vaccine yearly
|Increase penicillin to 250 mg twice daily from 3 years of age.||Hearing, vision, PPD as per standard practice||Dentist||Review all previous instructions.|
Medical identification bracelet
Give written baseline laboratory values to parent.
|> 5 years||Every 6 to 12 months||CBC and UA at least yearly|
BUN, creatinine and LFTs every 2 to 3 years
|Influenza vaccine yearly||Continue folic acid.|
Option to stop penicillin V
|Hearing, vision, PPD as per standard practice||Yearly retinal examination by ophthalmologist, beginning at 10 years of age||Review all previous instructions as needed.|
|Adolescence||Yearly||CBC and UA yearly|
BUN, creatinine and LFTs every 2 to 3 years
Ferritin or serum iron and TIBC at least once
|Influenza vaccine yearly||Medications as needed for chronic problems (e.g., hydroxyurea [Hydrea] for pain and to prevent or lower incidence of acute chest syndrome)||Hearing, vision, PPD as per standard practice||Annual Papanicolaou's smear for sexually active girls|
Yearly retinal examination by ophthalmologist
|Discuss sports participation, prompt care of leg abrasions and cuts, sexuality, pregnancy risk and contraception and genetic counseling.|
COUNSELING AND EDUCATION
The family physician should provide education and anticipatory guidance to help parents adjust to having a child with a chronic illness.13 The affected child should not be overprotected or neglected. Spouses and other children in the family need to have their share of attention, and they should be involved with, but not overwhelmed by, the care of the child with sickle cell disease.
During the early months of the child's life, emphasis should be given to teaching the mother and other caregivers how to recognize early signs of serious complications. It is also important to ensure that prophylactic measures, mainly penicillin and routine and special immunizations, are instituted in a timely fashion. Baseline laboratory values should be recorded during this period.
By the age of two months, the child should begin receiving orally administered penicillin V in a dosage of 125 mg twice daily. When the child reaches three years of age, the dosage is increased to 250 mg twice daily.5 Penicillin prophylaxis can be discontinued after the age of five years,14 except in the child who has had a splenectomy.
The new heptavalent conjugated pneumococcal vaccine (Prevnar) should be given from two months of age.15 The 23-valent unconjugated pneumococcal vaccine is mandatory from the age of two years (it is not effective below this age), and it can be boosted at least once three years later. After six months of age, children can begin receiving influenza virus vaccines yearly. The American Academy of Pediatrics recommends meningococcal vaccine for children with splenic dysfunction. All routine immunizations should be given in a timely fashion.
RECOGNITION OF COMPLICATIONS
All caregivers should be taught how to recognize specific signs and symptoms of illness. Because acute splenic sequestration crisis is a leading cause of death in young children with sickle cell disease, the family physician should carefully note the size of the child's spleen and teach the mother how to palpate for splenic size.
Caregivers must be told to seek immediate medical attention if the child develops any of the following: an enlarging spleen; temperature elevation; pallor of the skin, lips or nail beds; respiratory symptoms; and signs of pain or inability to move extremities. Caregivers should be told, however, that the child's earliest symptoms will most likely be painful swelling of the hands and/or feet (hand-foot syndrome). Taking precautions against dehydration, overexertion and exposure to cold can be preventive.
GROWTH AND DEVELOPMENT
The child's growth and development should be charted assiduously. Dietary advice should be specific, and multivitamin supplements fortified with maintenance quantities of iron are appropriate in early infancy. Folic acid can be given daily to ensure adequate amounts for the high erythrocyte turnover. Protein supplements can be given if weight gain lags markedly in infancy or growth and development lag in the peripubertal period.
Baseline values for hemoglobin level and hematocrit, reticulocyte count, white blood cell count, and liver and renal function should be recorded. These values should be checked periodically. It is a good idea to give the child's primary caregiver a copy of the baseline laboratory values so that this information can be shared with emergency department physicians as needed.
Iron levels should be measured in early infancy to ensure that the child does not have iron deficiency. Despite chronic hemolysis, iron deficiency can occur during periods of rapid growth if dietary iron intake is inadequate. However, therapeutic iron should not be given unless a deficiency is documented. Because children with sickle cell disease may have an increasing need for blood transfusions during childhood, they may eventually be at risk for iron overload rather than iron insufficiency.
Lead levels should also be obtained in accordance with accepted guidelines.
Periodic urinalysis is important because early signs of renal disease can be insidious. Findings of microscopic hematuria or persistent proteinuria should be investigated.
After the child reaches 10 years of age, careful retinal examinations should be performed by an ophthalmologist to rule out retinal disease.
TESTING RELATED TO SPECIFIC COMPLAINTS
Specific diagnostic tests are indicated if the child with sickle cell disease complains of severe or persistent headaches, recurrent right upper quadrant abdominal pain or pain in the hip or shoulder. Poor school performance should also be investigated.
Severe or persistent headaches warrant a careful neurologic examination. Even if the examination is normal, the child should undergo magnetic resonance imaging (MRI) and, if available, transcranial Doppler ultrasonography or magnetic resonance angiography.
If the child complains of recurrent right upper quadrant abdominal pain, an abdominal ultrasound examination should be performed to look for gallstones.
Pain in the hip or shoulder joint may indicate the onset of aseptic necrosis. Hip pain merits particular attention because of the weight-bearing function of this area. Radiography or MRI can aid in the diagnosis of aseptic necrosis.
Loss of classroom time because of illness is the most common cause of poor school performance in children with sickle cell disease. School problems may also be an early sign of central nervous system dysfunction.
ADOLESCENTS WITH SICKLE CELL DISEASE
Sickle cell disease can add to and complicate the problems young persons experience in adjusting to the mental and physical changes that occur during adolescence.16,17 Adolescents with sickle cell disease may have up to a two-year lag in growth and development. In addition, they must deal with often unpredictable absences from school or social functions because of illness.
Children and adolescents with sickle cell disease also must cope with restrictions on their physical activity. In general, they should be allowed to participate in any sport commensurate with their physical ability, but they must be careful to avoid overexertion, dehydration and extremes of temperature. They must learn to stop at the first sign of fatigue.
Adolescents should be reassured that they will have catch-up growth, so that their adult size will be in the average range. They need to know that they have only minor career limitations and that overall life expectancy for persons with sickle cell disease is increasing.
Adolescents with sickle cell disease should be given careful genetic counseling, as well as specific advice on contraception and family planning. They should also be encouraged to take charge of their disease, rather than have constraints thrust upon them.
Recommendations are best offered in the form of education of the adolescent about the disease, education of the family and the school about the needs of the adolescent, and preparation of the adolescent for the transition to adult life and adult medical care.13 In the case of the family physician, continuity of outpatient services for the adolescent is already in place, and the only requirement may be introduction of the adolescent to adult inpatient services at or before the time of hospitalization. There can be many differences between adult inpatient care and the highly nurturing environment of a pediatric service. Peer support groups can be particularly helpful for the adolescent.