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A 6 year old girl with sickle cell anemia, who is well known to ED personnel, presents with URI symptoms for 2 days, and fever to 38.9 (102 F). The URI symptoms consist of a stuffy nose, no rhinorrhea, and a dry cough, which has not interrupted her sleep. Oral intake has been decreased, but adequate. She has been given acetaminophen and over the counter cold medications. She also takes daily prophylactic amoxicillin.
Exam: VS T37.7, P 100, R 30, BP 98/52. She is nontoxic appearing. She has anicteric sclera, clear conjunctiva, mild clear white nasal discharge, a non-injected pharynx and normal TMs. No cough is heard during the exam. Her lungs are clear to auscultation. Her heart is regular without murmurs. Her abdomen is soft and non-tender to palpation. Her spleen in not palpated below the left costal margin, and her liver is palpated 2 cm below the right coastal margin. There are no rashes or skin lesions, and she moves all extremities well.
A CBC and blood culture are drawn. She is given IV fluids and IV ceftriaxone. Her primary care physician is contacted to discuss the case and to determine whether she should be hospitalized.
There are over 100 known hemoglobinopathies, but sickle cell disease remains the best described and is the prototype for all hemoglobinopathies. Sickle cell disease is a clinically significant condition which involves the sickle cell gene. Several forms of sickle cell disease exist: sickle cell anemia (the homozygous state, also known as SS disease), Hemoglobin SC disease, sickle beta thalassemia, and other rare entities. The heterozygous sickle cell state results in sickle cell trait. Such individuals are asymptomatic and have no significant medical problems. However, it is important for these individuals to be aware of their trait status for purposes of genetic counseling.
Sickle cell disease carries lifelong health considerations. Historically, 10% of children with sickle cell diseases died before their 10th birthday, most often due to overwhelming infection. Survival and morbidity have been unpredictable, largely due to problems with disease recognition and availability of medical care. Therefore, sickle cell diseases are now identified on the newborn screen in almost all states. This permits a proactive approach to the health maintenance of these patients, resulting in less morbidity and mortality.
The gene mutations for both sickle cell and hemoglobin C disease result in a single amino acid substitution on the beta globin chain. The normal beta globin chain has a glutamic acid in the codon 6 position. A valine substitution here results in hemoglobin S, while a lysine substitution in the same position results in hemoglobin C. Both conditions are autosomal recessive. A single sickle cell gene is carried by about 10% of African Americans and the gene for Hemoglobin C is carried by about 2% of African Americans. Sickle cell disease can be easily detected on hemoglobin electrophoresis. The normal hemoglobin electrophoresis in a person greater than 6 months of age shows about 92.5% Hemoglobin A, which consists of 2 alpha globin chains and 2 beta globin chains, and about 2.5% hemoglobin A2 which consists of 2 alpha chains and 2 delta chains. Since the sickle cell gene produces an abnormal beta globin chain, hemoglobin S is comprised of 2 alpha globin chains and 2 abnormal beta globin chains. In the heterozygous state, the normal beta globin gene produces sufficient beta globin chains to produce enough normal hemoglobin A (asymptomatic heterozygous state). Likewise, hemoglobin C consists of 2 alpha globin chains and 2 abnormal beta globin chains. Both hemoglobin S and hemoglobin C are also easily picked up on the newborn screen, which utilizes methods that separate out and identify various hemoglobins, abnormal and normal alike. Hemoglobin F (fetal hemoglobin) predominates in the normal newborn, and is completely replaced with hemoglobin A by 6 months of age. Hemoglobin F consists of 2 alpha globin chains and 2 gamma globin chains. Since hemoglobin F has no beta globin chains, it is not affected by the sickle cell gene. The normal adult or child produces less than 1% hemoglobin F. On the newborn screen, hemoglobin S is identified quantitatively at birth in its relation to hemoglobin F. If more hemoglobin S than F is present, the child most likely has sickle cell disease. If more hemoglobin F than S is identified, the child likely has sickle cell trait.
Sickle cell anemia occurs when both alleles of the beta globin gene on chromosome 11 are affected by a single amino acid substitution of valine for glutamic acid (resulting in hemoglobin S). Such children produce no normal hemoglobin A. Instead, they produce hemoglobin S. The presence of hemoglobin S within the red blood cells causes an unnatural stiff folding, or sickling of the red blood cell, especially under conditions of oxidative stress. These sickled cells have a tendency to stack up on one another, and thus causes intravascular clogging in the microvasculature. This in turn leads to a vascular occlusion crisis with infarction of local tissue, and severe pain (vaso-occlusive crisis). Hydration is the mainstay of treatment for such crises. The presence of sickle hemoglobin alone, decreases erythrocyte survival leading to chronic hemolytic anemia. It is always important to know a sickle cell patient's baseline hemoglobin when they are well (while not having an obvious vaso-occlusive crisis). The clinical syndromes as a result of this sickling vary depending on whether one is seeing a pediatric or adult patient.
Sickle cell anemia does not present clinically before 6 months of age because of the protective effect from the uninvolved Hemoglobin F. But after 6 months of age, the usual clinical manifestations include infection (usually respiratory), failure to thrive, unexplained fever, and irritability. Before routine newborn screening for sickle cell disease, young children often presented with dactylitis (hand-foot syndrome), which is a swelling of the dorsum of the hands or feet, associated with pallor and fever. Since appropriate and prompt attention is given to symptoms such as fevers, pain, and swelling without a delay in diagnosis, children presenting with dactylitis from sickle cell anemia has become mostly a thing of the past.
The pediatrician is most often confronted with infectious complications of sickle cell anemia. These children are especially prone to bacterial infections such as pneumococcus, Haemophilus influenzae B and Salmonella. Historically, infections have been the primary cause of death during early childhood. Since fevers alone can increase sickling, any febrile child with sickle cell anemia should be given IV hydration to prevent further sickling, and empiric antibiotic therapy should be strongly considered (after appropriate cultures are taken). One reason for the high rate of infections in children with sickle cell disease is that they are functionally asplenic. Because the spleen acts as a sponge for these abnormal sickled cells, subclinical intermittent episodes of intrasplenic vaso-occlusion occur causing local splenic infarcts. Therefore, by the age of 8 years, sickle cell patients are completely functionally asplenic (due to infarction). All sickle cell patients are given prophylactic penicillin, especially during childhood. Additionally, by now identifying children with sickle cell disease at birth, prophylactic pneumococcal vaccine, plus strict attention to the routine childhood vaccinations have been shown to dramatically decrease childhood morbidity and mortality from infection.
Rarely, infants have massive splenic congestion of red blood cells called the splenic sequestration crisis. When this occurs, it is frequently fatal, since it rapidly removes enormous amounts of red blood cells from the circulation, which can lead to circulatory collapse.
A pain crisis is one of the most common reasons for hospitalizing an older child with sickle cell anemia. In a pain crisis, a specific limb or other body part is affected by the vaso-occlusive effects of the sickling cells in the microvasculature. The biggest challenge to the treating clinician in managing this condition, is to administer sufficient analgesia to stop the pain. This is problematic for a variety of reasons: fear of narcotic addiction on either the family's part or the caregiver's part, belief that the pain cannot be controlled completely, belief that some patients exaggerate their pain, and lack of quick access to appropriate analgesics. Success in treating a painful crisis is reached when the analgesic is effective in stopping the pain. Standard doses of analgesics may not be sufficient. Many painful crises can be managed at home with oral analgesics and oral hydration. However, other such crises require IV hydration and IV narcotic analgesics. In these cases, a continuous infusion of a narcotic such as hydromorphone (Dilaudid) with a PCA (patient controlled analgesia) pump is far superior to a "Q 3 hour prn pain" regimen. Meperidine (Demerol) should never be used because patients receiving this have a higher incidence of seizures. There is presently no role for serial intramuscular analgesic injections for pain management.
Acute chest syndrome is another common reason for hospital admission in the older child. Clinically, this is an acute pneumonia-like illness characterized by fever, dyspnea, chest pain, and fatigue. It is usually caused by local pulmonary infarction from vaso-occlusive sickling. Often, acute chest syndrome is complicated by Mycoplasma pneumonia.
Another unique complication of sickle cell disease is aplastic crisis, especially erythroid aplasia. This is often the direct result of human parvovirus infection. Other complications of sickle cell disease include devastating cerebral strokes, leg ulcers, bone infarction, bone marrow hyperplasia, priapism, gallstones, biliary tract disease, or splenic sequestration crisis in the young child.
Hydration is the mainstay of treatment for vaso-occlusive crises, pain crises, strokes, and infections associated with sickle cell disease. Vigorous intravenous hydration should be given to the very young child (<5 years). Above this age, outpatient oral hydration can be considered for mild complaints only. Intravenous hydration with at least twice maintenance fluids, after deficits are corrected, is mandatory in treating dehydration, and strongly recommended in all other situations.
Prevention of the clinical symptoms associated with sickle cell anemia is not considered a universal goal because, unlike other hemoglobinopathies, the clinical course of each patient is unpredictable. An individual patient can go for years without any significant problems, and then have many crises for months or years. Allogenic bone marrow transplantation (from an unaffected donor) would cure the patient of sickle cell disease, but such a transplant is done most safely in infancy, before one knows what that individual's sickle cell course, and its morbidity, will be. Allogenic transplantation carries its own serious morbidity (graft versus host reaction, immunosuppression, etc.), thus it is impossible to predict the risk/benefit ratio for an individual patient. Bone marrow transplantation in an older child would only be considered in the presence of significant morbidity from sickle cell disease itself. However, at that point, end organ tissue damage has occurred, further increasing the morbidity of transplantation. Thus, allogenic bone marrow transplantation is not a good strategy for sickle cell disease.
It has been shown that patients with sickle cell anemia become clinically asymptomatic if the amount of Hemoglobin S in the circulating blood is less than 30%. One way to accomplish this is to transfuse children with normal red blood cells, thereby diluting down their amount of Hemoglobin S, and also shutting off their own hematopoiesis to a large degree. Thus, children with significant morbidity can be placed on a transfusion protocol, in which patients are transfused about every 2 to 4 weeks, indefinitely. The goal of transfusion therapy is to lower the percentage of hemoglobin S to <30% at all times, and to keep the hematocrit below 46%, reducing blood viscosity. With this, there is no further clinically significant sickling. The main hindrance to a transfusion protocol is iron overload. Without chelation, iron overload is eventually fatal (due to hemochromatosis). Currently, chelation involves nightly 10 hour subcutaneous infusions of deferoxamine as long as the transfusions continue. Poor compliance is an issue, especially in the teen years. Additionally, alloimmunization to blood products can develop in some patients. This creates greater difficulty in obtaining compatible blood products causing a higher incidence of delayed hemolytic reactions.
Other methods to decrease the relative amount of hemoglobin S are currently under investigation. Such methods are met with only varied individual success. Hydroxyurea has been shown to increase the percentage of Hemoglobin F (which lacks abnormal beta globin and does not sickle), thereby creating a relative decrease of Hemoglobin S. This is an oral medication with few other side effects and would seem to be an attractive therapeutic option. Unfortunately, it has not been shown to be consistently effective in reducing either the frequency or severity of symptoms in these patients.
Children with hemoglobin SC disease have one beta-C mutation on one allele and one beta-S mutation on the other. Hemoglobin SC disease is typically associated with milder and less frequent vaso-occlusive events compared to sickle cell anemia. However, like sickle cell anemia, the clinical course can be quite variable. Typically, patients go for years between clinically significant events. They usually have a higher hematocrit than those with sickle cell disease, as they have a less chronic hemolysis. Children with SC disease should receive the same prophylactic care as those with sickle cell anemia.
Likewise, sickle beta thalassemia, in general, is associated with milder symptoms than sickle cell disease, although the clinical severity depends on the type of beta anomaly present. If the beta gene is deleted, the degree of morbidity is similar to patients with homozygous sickle cell disease. If the beta gene is present but abnormal, then the clinical severity tends to be milder, comparable to SC disease.
1. Of the following, what is the best approach for a febrile child with sickle cell disease?
. . . . . a. CBC, BC, oral hydration, IM or oral antibiotics if source of infection is noted on PE.
. . . . . b. CBC, BC, IM ceftriaxone, follow-up with PCP next day.
. . . . . c. CBC, BC, admit for IV hydration and IV antibiotics.
. . . . . d. CBC, BC, no oral antibiotics if no specific source of infection is noted on PE.
2. A 13 year old girl with sickle cell anemia is admitted to the hospital for treatment of a pain crisis. She states her right arm and shoulder started hurting yesterday evening. She has taken acetaminophen with codeine every 3 hours for the last 8 hours, but the pain has only escalated. She denies recent fevers, cough, or URI symptoms. She is on no routine pain medications at home, and was last admitted 5 months ago with a similar pain crisis. On PE, she is in obvious pain, and is crying. Her exam is remarkable for pallor, and slight scleral icterus. She has full range of motion of the right arm, and the rest of her joints. CBC shows a hemoglobin of 7.9 g/dl, WBC 17.8, and platelet count of 543 thousand. Appropriate initial management includes:
. . . . . a. IV hydration if oral intake is insufficient, IV or PO pain management as needed.
. . . . . b. IV hydration, hydromorphone PCA plus continuous infusion.
. . . . . c. IV hydration, IM meperidine prn.
. . . . . d. IV hydration, transfusion of PRBC, IV narcotic q 4 hours prn.
3. Explain why most states have adopted newborn screens that identify sickle cell disease at birth.
4. Explain why children with sickle cell disease do not develop symptoms until after 6 months of age?
5. Will a child with sickle beta thalassemia be identified as such on its newborn screen? Why or why not?
1. Wethers WY. Sickle cell disease in childhood: Part I. Laboratory Diagnosis, pathophysiology and health maintenance. Am Fam Physician 2000;62(5):1013-1020,1027-1028.
2. Wethers DL. Sickle cell disease in childhood: Part II. Diagnosis and treatment of major complications and recent advances in treatment. Am Fam Physician 2000;62(6):1309-1314.
3. Steinberg MH. Review: Sickle cell disease: present and future treatment. Am J Med Sci 1996;312(4):166-174.
4. Dreyer ZE. Chest infections and syndromes in Sickle cell disease of childhood. Semin Respir Infec 1996;11(3):163-172.
Answers to questions
1.c. This fever is significant, thus there will be an increase in sickling, and the patient is at risk for vaso-occlusive events. Therefore, IV hydration is necessary. It is also prudent to start empiric antibiotics after blood cultures are obtained.
2.b. Appropriate initial management should include vigorous IV hydration, plus IV pain management to include both a continuous infusion and a PCA. One would not transfuse initially, because a transfusion of packed red blood cells will only increase the viscosity of the blood, causing more sickling. Also, one does not know at this point, what the baseline hemoglobin is. The hemoglobin of 7.9 g/dl may not be very different than baseline. If there is further hemolysis, and a transfusion is indicated, it should be done carefully after several hours of IV hydration. Also, remember that meperidine increases seizure activity in children with sickle cell anemia, and is contraindicated.
3. It has been shown that a proactive approach to sickle cell disease decreases morbidity and mortality. Therefore, by identifying all children with sickle cell disease at birth, before symptoms start (usually after 1 year of age), quality of life can be improved.
4. Only after 6 months of age is gamma globin chain production decreased and beta globin chain production sufficient to cause sickling.
5. No. Both beta and sickle anomalies are on the beta globin gene. The newborn screen will identify the sickle hemoglobin, but will not identify the abnormal beta globin genes. The newborn screen will therefore appear as that for sickle cell trait with Hemoglobins F,A, S.