Etiology
Sickle cell diseases are a group of genetic disorders with various clinical manifestations; the common feature is that the affected individuals have at least one gene for Hb S. The disorders include homozygous Hb SS disease and disease states in which Hb S is associated with other variant Hbs (e.g., Hb SC, Hb SD, Hb S/β thalassemia) that enhance or promote the sickling phenomenon
(Table 55.2). Sickle cell disease is identified in most cases by newborn screening. Confirmation of the diagnosis is by Hb ELP.
The cause of sickle cell disease is a mutation in the β-globin gene. An adenine-to-thymine substitution in codon 6 of the β-globin gene specifies the insertion of valine for glutamic acid at the sixth position of the β-globin chain to produce Hb S. Hb S occurs frequently among population in areas previously exposed to falciparum malaria, including western coastal Africa, central Africa, India, Saudi Arabia, and the Mediterranean countries. Hb S in these patients provides protection against intraerythrocytic growth of malaria.
Pathophysiology
Hb S crystallizes and polymerizes on deoxygenation, thereby distorting the RBC. Polymerization and distortion lead to destruction of the RBC membrane, decreased RBC deformability, and increased RBC adhesion to vascular endothelium. Sickling of erythrocytes is facilitated by fevers, dehydration, and acidosis.
The clinical problems associated with sickle cell disease are a consequence of hypoxia and acidosis, which are caused by tissue ischemia resulting from vaso-occlusion by irreversibly sickled RBCs. The clinical manifestations include severe hemolytic anemia, an increased frequency and severity of certain infections, tissue infarction with subsequent organ damage and failure, and recurrent episodes of pain. The clinical manifestations are acute and chronic.
Clinical Presentations and Treatments
Sickle cell disease is a chronic condition in which acute events of variable severity occur intermittently. Patients require care in specialized centers. Routine health maintenance is important, with an emphasis on nutrition, education of families, infection prophylaxis, and anticipatory guidance regarding the avoidance of extremes of temperature, dehydration, and physical activity
(Table 55.3).
The clinical consequences of sickle cell disease can be broadly grouped into three categories:
Vaso-occlusive events
Hemolytic events
Infectious events
The damage inflicted by sickle cell disease can be acute or chronic in nature.
Vaso-occlusive Crisis
Vaso-occlusive crisis occurs when poor RBC deformability, increased viscosity, and adherence of the “sickled” RBCs to endothelial cells cause ischemia/infarction. Vaso-occlusive crisis is also known as pain crisis. It most commonly affects bone, lung, liver, spleen, brain, and penis.
Bone infarction or ischemia of the periarticular tissues is the most common form of acute vaso-occlusive pain crisis. The pain is usually diffuse. Localized tenderness, swelling, and limited range of motion are common. Redness and warmth occur but are not prominent. Low-grade fevers usually develop. The severity and frequency of pain crisis increase with age. Initially, pain crisis is usually dactylitis (hand-foot syndrome), most common in children <2 years and involving the metacarpals, metatarsals, and phalanges of one or more extremities. Long bones, spine, clavicles, ribs, and sternum are also frequently affected by pain crisis. Treatment is supportive, with aggressive hydration, narcotic analgesics, and nonsteroidal anti-inflammatory agents. Oxygen is of little value and may actually exacerbate anemia. Infection should be sought out and treated.
Cerebrovascular Events
Two major central nervous system (CNS) complications of Hb SS disease are occlusion in large vessels and aneurysms in small vessels. Stroke occurs in up to 15% of patients with Hb SS, and the reported mortality is 15% to 20%. It is the second leading cause of death in patients with Hb SS. The risk of stroke is four times higher in patients with Hb SS disease compared with patients with Hb SC disease. Stroke is usually the result of infarction, although hemorrhagic strokes do occur. Sickling of RBCs in the vas vasorum of the large vessels leads to infarcts in the blood vessel walls causing stenosis, aneurysms, and occlusion. The distribution is typically the middle cerebral artery and watershed areas, and the stroke may be preceded by a transient ischemic attack.
The presentation is with seizures, paresis, or aphasia. Various findings are noted on magnetic resonance imaging (MRI), computed tomography (CT) scan and arteriography. The recurrence rate without treatment is 70% within 3 years.
Treatment involves reducing the concentration of Hb S to 30% to 50%; this usually requires exchange transfusion but can sometimes be accomplished by a simple transfusion. Erythrocytapheresis is the preferred treatment in an acute event to rapidly reduce the concentration of Hb S.
Chronic transfusion of RBCs by hypertransfusion or erythrocytapheresis is mandatory to decrease or prevent the recurrence of stroke. Recovery varies, although children recover more fully than adults. A recent study by the National Institutes of Health has concluded that it is not safe to stop
RBC transfusions even after 5 years in this patient population due to the risk of stroke recurrence.
It is important to note that 30% of asymptomatic patients with Hb SS disease have “silent” infarcts on MRI surveillance. These patients have never had clinical evidence of stroke. Children with Hb SS disease should have transcranial Doppler (TCD) ultrasonography every 6 months or at least once a year starting at the age of 2 years. TCD measures the velocity of blood flow through the internal carotid and middle cerebral arteries. More frequent studies should be done on patients with borderline high velocities (180-199 cm/second). If the velocity is ≥200 cm/second on two separate occasions 1 to 2 months apart, magnetic resonance arteriography and venography should be done to assess the patient’s risk for stroke. If the patient has tortuous vessels with or without stenosis, moyamoya disease (basal arterial occlusion with telangiectasia), and/or “silent” infarct(s), then commencing a chronic RBC transfusion program is strongly recommended.
The long-term consequences of chronic transfusion program are the result of iron overload and alloimmunization. Iron chelation therapy should be administered in children 3 years and older when the serum ferritin is >1000 ng/mL (although serum ferritin alone is not a reliable measure of total body iron burden). Deferoxamine is currently the standard chelating agent. Partial RBC exchange transfusions are another approach to reducing iron overload.
Acute Chest Syndrome
Patients present with chest pain, tachypnea, shortness of breath, cough, fever, leukocytosis, unilateral or bilateral
infiltrates, and possibly hypoxemia. Bony tenderness over the ribs, sternum, or spine may occur. Bloody or purulent cough is not prevalent. Increased incidence of acute chest syndrome occurs in patients with low fetal hemoglobin, high steady-state hemoglobin (increased blood viscosity), high white blood cell counts, and in the winter months when the frequency of respiratory infections are increased. Acute chest syndrome may develop after vaso-occlusive pain crisis, which is a consequence of infarcts in long bones creating pulmonary fat emboli. The Hb level can be significantly decreased from baseline at presentation. The respiratory status can quickly deteriorate as hypoxia and acidosis further promote sickling.
Causes of acute chest syndrome include infection, bone infarction, and the formation of fat emboli secondary to bone marrow necrosis. The fatality rate is 10% to 20%; acute chest syndrome is reported to be the leading cause of death in patients with Hb SS disease who are >10 years. It is the most common complication of anesthesia. Repeated episodes can lead to chronic restrictive pulmonary disease, pulmonary hypertension, and cor pulmonale. Early recognition is important. Treatment includes:
Correction of the hypoxemia with oxygen
Administration of antibiotics and analgesics
Transfusion (simple or exchange)
Incentive spirometry to prevent hypoventilation
Priority should be given to administering RBC transfusions to rapidly decrease Hb S. Intravenous fluids should not exceed maintenance rate. A rapidly deteriorating patient should have exchange transfusion (erythrocytapheresis). These patients can progress to respiratory failure and require tracheal intubation and ventilator support. A multicenter acute chest syndrome trial conducted by the National Institutes of Health accrued 538 patients with 671 episodes of acute chest syndrome. Analysis of bronchial alveolar lavage samples from these patients revealed the following:
30%: negative for viral, bacterial, and fungal infection
16%: positive for lipid-laden macrophages (pulmonary fat emboli)
54%: positive for infection (Chlamydia 13%), (Mycoplasma 12%), (viruses 12%), (Staphylococci, Streptococci, and Haemophilus 8%)
Empiric intravenous antibiotic therapy should include a 3rd generation cephalosporin, such as ceftriaxone or cefotaxime and a macrolide.
