In the Clinic

Sickle Cell Disease

Screening Diagnosis and Evaluation Treatment and Management Patient Education Practice Improvement Tool Kit Patient Information CME Questions
Section Editors Deborah Cotton, MD, MPH Darren Taichman, MD, PhD Sankey Williams, MD Physician Writer Martin H. Steinberg, MD

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The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including PIER (Physicians Information and Education Resource) and MKSAP (Medical Knowledge and SelfAssessment Program). Annals of Internal Medicine editors develop In the Clinic from these primary sources in collaboration with the ACPs Medical Education and Publishing divisions and with the assistance of science writers and physician writers. Editorial consultants from PIER and MKSAP provide expert review of the content. Readers who are interested in these primary resources for more detail can consult http://pier.acponline.org, http://www.acponline.org/products_services/ mksap/15/?pr31, and other resources referenced in each issue of In the Clinic. CME Objective: To review current evidence for the screening, diagnosis and evaluation, treatment and management, patient education, and practice improvement for sickle cell disease. The information contained herein should never be used as a substitute for clinical judgment. 2011 American College of Physicians

In theClinic

Common Genotypes of Sickle Cell Disease

HbA is the major normal adult hemoglobin. Sickle cell anemia: homozygosity for the HbS or sickle hemoglobin gene HbSC disease: compound heterozygosity for HbS and HbC genes HbS-thalassemia: compound heterozygosity for HbS and a 0- or +-thalassemia gene HbSO Arabia: compound heterozygosity for HbS and HbO Arabia HbSD Los Angeles (Punjab): compound heterozygosity for HbS and HbD HbSE: compound heterozygosity for HbS and HbE

ickle cell disease is a Mendelian genetic disorder caused by several common genotypes (see the Box: Common Genotypes of Sickle Cell Disease). Sickle cell trait is clinically benign and should not be considered a disease.

Many other compound heterozygotes have been described. Most are rare, and only a few have a clinical phenotype. A single point mutation in the -hemoglobin gene (HBB) is responsible for the synthesis of sickle hemoglobin (HbS, 2S2). At least 50% HbS is present in all genotypes of sickle cell disease. Polymerization of deoxy sickle hemoglobin injures the sickle erythrocyte. Damaged sickle cells die prematurely, mainly by being caught in the reticuloendothelial system, but some hemolyze intravascularly. Sickle erythrocytes occlude blood vessels of all sizes. The complex pathophysiology resulting from sickle vasoocclusion and hemolytic anemia includes, at a minimum, abnormal erythrocyte volume regulation, impaired nitric oxide bioavailability, reperfusion injury, inflammation and oxidant damage, abnormal intercellular interactions, endothelial injury, and leukocyte and platelet activation. In sickle cell trait, HbS levels are 40% or less of total hemoglobin. As a result, in normoxic conditions these cells do not deform when they are deoxygenated, except in the renal medulla where pH and oxygen levels are low and the solute concentration is high (see below). In African Americans, the incidence of sickle cell anemia at birth is estimated to be approximately 1 in 600, and the incidence of all genotypes of sickle cell disease approaches 1 in 300. These estimates are influenced by increasing immigration from the Caribbean region, Central and South America, the Middle East, Africa, and India. Given the distribution of the HbS gene in the worlds population, determining which individuals are at risk for sickle cell disease is difficult. Whereas the HbS gene is most prevalent in persons of African, Arabian, and Asian-Indian ancestry, genetic admixture ensures its presence in most ethnic groups, albeit at a far lower prevalence.

Screening
1. 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;44:1428-33. [PMID:17479937] 2. Adams R, McKie V, Nichols F, et al. The use of transcranial ultrasonography to predict stroke in sickle cell disease. N Engl J Med. 1992;326:60510. [PMID:1734251] 3.Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998;339:5-11. [PMID:9647873]

Who should be screened for sickle cell anemia and sickle cell trait and at what age? What methods should be used? In the United States, all newborns are screened for sickle cell disease. After confirmation of the screening results, state health departments refer patients to a medical facility for follow-up and parents are taught to recognize splenic sequestration and signs of sepsis, as this can reduce the morbidity and mortality of these complications. Patients are then given pneumococcal vaccination and penicillin prophylaxis, at least to age 5 years. Although this has decreased the overall incidence of childhood infection, in 1 study only 25% to 30% of patients received prophylactic penicillin for at least 270 days per year, impairing the effectiveness of this approach (1).

Transcranial Doppler blood flow screening can detect children at risk for stroke, and they should have initial screening starting at age 2 years (2). Identification of patients at risk should trigger the start of a long-term transfusion program that reduces risk for stroke by more than 90% (3). Newborn screening also detects carriers of the sickle cell trait. Parents of these individuals are usually notified, and counseling is provided in some states. Outside of newborn screening programs, screening the general population for sickle cell trait is not indicated, but instead should be limited to individuals believed to be at risk who are pregnant or planning a pregnancy and in those who have hyphema (bleeding into the anterior

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chamber of the eye) or hematuria. As with all genetic diseases, determining who is at risk can be difficult. A careful and sensitive maternal and paternal family history is the best guide for determining appropriate individual screening for HbS. What specific screening and diagnostic tests should be done in newborns, children, and adults suspected of having sickle cell disease or sickle cell trait? Screening to detect HbS in newborns, children, and adults is usually done by high-performance liquid chromatography (HPLC), although some laboratories screen by using isoelectric focusing. When genetic counseling is needed, direct detec-

tion of the HbS and other globin gene mutations by DNA-based techniques is usually warranted. What tests are available for prenatal diagnosis of sickle cell disease? Establishing the parental globin gene mutations by DNA-based testing is a prerequisite for prenatal diagnosis. If positive, then DNAbased testing of chorionic villus samples or amniotic fluid cells is performed. Before considering prenatal diagnosis, parents should be counseled about the risks of the procedure, the consequences of a positive diagnosis, the likelihood of an affected fetus, and options for termination.

Screening... Screening can lead to prompt diagnosis of sickle cell anemia, prevention of serious complications, and provide information for family planning.

CLINICAL BOTTOM LINE

What presenting symptoms and illnesses should prompt consideration of undiagnosed sickle cell disease? Sickle cell disease can be missed in persons born before newborn screening was implemented. Consideration of sickle cell disease should occur when careful history-taking suggests frequent unexplained episodes of pain. The physical examination may show splenomegaly. Screening should also be done in patients who have had a stroke at a relatively young age or who developed pneumonia with anemia requiring transfusion. Strokes occur in about 10% of children and adults with sickle cell anemia (4) but are much less common in other genotypes of the disease. Osteonecrosis of the heads of the femur and humerus is found in about half of all adults with sickle cell disease. Severe complications that are rarely part of the initial presentation are leg ulcers, priapism,

nephropathy with renal failure, and severe anemia. Other complications that tend to occur with advancing age are sickle retinopathy, especially in HbSC disease, and liver disease. Infections are common and a major cause of death in children and adults. The widespread vasculopathy of sickle cell disease can be screened for by estimating the tricuspid regurgitant jet velocity (TRV). Elevated values portend early mortalityat least 25% of patients with this complication die within 2 years of detection (5). Other than dyspnea, there is no history that suggests pulmonary hypertension. Most persons with sickle cell anemia and HbS0-thalassemia require medical attention very early in life. In contrast, the clinical features of HbSC disease and HbS+-thalassemia can be quite mild, delaying diagnosis until a critical complication occurs or its presence is detected incidentally (6).

Diagnosis and Evaluation

4. Strouse JJ, Jordan LC, Lanzkron S, Casella JF. The excess burden of stroke in hospitalized adults with sickle cell disease. Am J Hematol. 2009;84:548-52. [PMID: 19623672] 5. Parent F, Bachir D, Inamo J, Lionnet F, Driss F, Loko G, et al. A hemodynamic study of pulmonary hypertension in sickle cell disease. N Engl J Med. 2011;365:44-53. 6. Steinberg MH, Nagel RL. Hemoglobin SC Disease and Hemoglobin C Disorders. In: Steinberg MH, Forget BG, Higgs DR, Weatherall DJ, eds. Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. 2nd ed. Cambridge: Cambridge University Press; 2009:525-48

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7. Kark JA, Ward FT. Exercise and hemoglobin S. Semin Hematol. 1994;31:181-225. [PMID:7973777] 8. Kark JA, Posey DM, Schumacher HR, Ruehle CJ. Sickle-cell trait as a risk factor for sudden death in physical training. N Engl J Med. 1987;317:781-7. [PMID:3627196] 9. Steinberg MH, Barton F, Castro O, et al. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA. 2003;289:1645-51. [PMID:12672732] 10. Steinberg MH, McCarthy WF, Castro O, et al. The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: A 17.5 year follow-up. Am J Hematol. 2010;85:403-8. [PMID:20513116] 11. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med. 1995;332:131722. [PMID:7715639] 12. Voskaridou E, Christoulas D, Bilalis A, et al. The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS). Blood. 2010;115:2354-63. [PMID:19903897]

What should be looked for on the physical examination when sickle cell disease is suspected? Swelling and tenderness over affected areas and low-grade fever are common in acute, painful episodes. Consolidation, rales, rhonchi, and wheezing are found with the acute chest syndrome. Sickle retinopathy is often difficult to detect by direct retinal examination and can require referral to an ophthalmologist for indirect retinoscopy and fluorescein angiography. Cardiac enlargement and systolic murmurs are common; the liver is often enlarged. Most adults with sickle cell anemia are asplenic and do not have splenic dullness on percussion. Patients with HbSC disease and HbSthalassemia can have splenomegaly. What laboratory tests should be ordered in the evaluation of possible sickle cell disease? In untreated sickle cell anemia, the erythrocytes are normocytic or macrocytic, depending on the reticulocyte count and the presence or absence of confounding conditions like iron or folic acid deficiency and coincident -thalassemia. Microcytosis in adults with sickle cell anemia can be seen when iron deficiency has developed or when coexistent -thalassemia is present. HbS0thalassemia is a phenocopy of sickle cell anemia with microcytosis and high levels of HbA2, and it is difficult to differentiate from sickle cell anemia and sickle cell anemia with coincident -thalassemia without genetic testing or family studies. These differences are mainly important for genetic counseling because management of these genotypes is the same. A sickle solubility test is insufficient as the sole means of diagnosing sickle cell disease. High-performance liquid chromatography is the best screening method. It is automated and accurate and reliably measures the levels of HbS, HbA2, and HbF.

The levels of HbF are a guide to the efficacy of hydroxyurea treatment (see below) and have some prognostic value; HbA2 levels are increased in -thalassemia (Table 1). After a diagnosis is established, baseline tests should include complete blood counts and reticulocyte counts; red cell antigen phenotyping; measurement of blood urea nitrogen, creatinine, urine albumin, electrolytes, bilirubin, lactate dehydrogenase (LDH), serum ferritin, alanine transaminase, aspartate transaminase, and alkaline phosphatase levels; chest radiographs; pulmonary function tests; pulse oximetry; and echocardiography to estimate the TRV. The availability of this information at baseline assists in interpreting laboratory results during an acute complication or to document organ damage over time. What are the complications of sickle cell trait? About 8% of African Americans have sickle cell trait. Their blood counts are normal, and they do not have excess mortality. Activities do not need to be restricted. Because of renal medullary abnormalities, most carriers cannot concentrate urine normally but this is not a problem if hydration is adequate. Hematuria is increased in trait carriers and is usually due to papillary necrosis but is usually benign and self-limited. Nevertheless, it could arise from more ominous causes. Renal medullary cancer in young patients, stones, glomerulonephritis, and infection should be excluded during the evaluation of hematuria. Splenic infarction in African Americans with sickle cell trait is rare, or at least rarely reported. This complication was reported in African runners with trait who competed at high altitudes. Caucasian men with sickle cell trait may be overrepresented in reports of altitude-induced sickle cell splenic syndrome because of the perceived novelty of the association of splenic infarction and sickle cell trait in

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Table 1. Laboratory Findings in Common Forms of Sickle Cell Disease*

Genotype PCV (%) Reticulocyte MCV (fL) count (5) HbS (%) HbF (%) HbA2 (%)

Sickle cell anemia HbSC disease HbS+-thalassemia HbS0-thalassemia Sickle cell trait Normal

25 35 35 28 3848 3848

10 2 2 10 1 1

90 80 70 75 85 85

91 47 70 89 40 0

6 2 2 6 1 1

3 3 5 5 2.5 2.5

Hb = hemoglobin; MCV = mean corpuscular volume; PCV = packed cell volume. *Average values for adults in a steady state remote from an acute event and for those not receiving hydroxyurea treatment. For more detailed information, see reference 6. Remainder of hemoglobin is HbC. Remainder of hemoglobin is HbA.

Caucasians. Carriers of the sickle cell trait safely tolerate anesthesia and surgery, and use of a tourniquet in orthopedic procedures seems to be safe. Because anesthetic risk is not increased and surgery is safe, there is no rationale for routine preoperative screening for sickle cell trait. An exception might be open-heart surgery or complicated intrathoracic procedures where hypoxia is intrinsic to the procedure. Although controlled studies have not been reported, preoperative screening and transfusion may be prudent in these cases. African Americans with sickle cell trait have a 2-fold increased risk for thromboembolic disease and a 4fold risk for pulmonary embolism. Reports of sudden death or lifethreatening episodes during exercise in sickle cell trait have been extensively reviewed (7). Most were attributed to exertional heat illness, rhabdomyolysis, and idiopathic sudden death. During a 5-year period, the risk for sudden unexplained death was higher in black military recruits with sickle cell trait compared with those without the trait. Compared with black recruits without sickle cell trait and whites, the relative risk was 40 (8). When a policy of gradual conditioning, liberal fluid intake, and avoidance of overexertion under all conditions especially increased temperature and humiditywas adopted, the death rate in persons with the sickle cell

trait was said to decrease to that of the overall population of recruits. A currently contentious issue is screening for sickle cell trait, especially in athletes. Based on the total body of work on exercise ability and capacity, there is no reason to restrict exercise of any type in persons with sickle cell trait. All individuals engaged in strenuous exercise, trained or untrained, should be properly conditioned and clothed, have unrestricted access to fluids, have appropriate rest periods, moderate the exercise routine to adjust for excessive heat and humidity, and receive rapid treatment if symptoms develop. There is no physiologic evidence that carriers of sickle cell trait have exercise-induced sickling that can be recognized clinically and reversed rapidly. Which patients with sickle cell disease should be referred for consultation with a specialist? All patients with sickle cell disease should have at least yearly evaluations by a hematologist with special competence in hemoglobinopathies. Such specialists are best trained to begin treatment with hydroxyurea or long-term transfusion or to manage refractory pain and organ dysfunction. Such pulmonary complications as hypertension require consultation with a pulmonologist or cardiologist familiar with diagnosis and treatment of this condition.

13. Brawley OW, Cornelius LJ, Edwards LR, et al. National Institutes of Health Consensus Development Conference statement: hydroxyurea treatment for sickle cell disease. Ann Intern Med. 2008;148:932-8. [PMID:18458271] 14. Hankins JS, Ware RE, Rogers ZR, et al. Long-term hydroxyurea therapy for infants with sickle cell anemia: the HUSOFT extension study. Blood. 2005;106:2269-75. [PMID:16172253] 15. Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet. 2011;377:1663-72. [PMID:21571150] 16. Ferster A, Tahriri P, Vermylen C, et al. Five years of experience with hydroxyurea in children and young adults with sickle cell disease. Blood. 2001;97:3628-32. [PMID:11369660] 17. Vichinsky EP, Haberkern CM, Neumayr L, et al. A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. The Preoperative Transfusion in Sickle Cell Disease Study Group. N Engl J Med. 1995;333:206-13. [PMID:7791837]

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Common Complications of Sickle Cell Disease

Acute painful episode: >90% of patients Acute chest syndrome: >50%, sometimes lethal Stroke: 10% of children and adults, neurocognitive damage Osteonecrosis: about 30% of patients, crippling, painful Proliferative retinopathy: 30% in HbSC disease Splenic infarction, sequestration: in children and adults with HbSC disease Priapism: >30% of males Leg ulcers: 10%30%, painful, destructive; rare in HbSC Infection: pneumococcal, gramnegative sepsis Psychosocial issues

As sickle cell disease is a systemic disorder, consultations with urologists, ophthalmologists, orthopedists, general surgeons, gastroenterologists, nephrologists, and endocrinologists are often required. Severe cases of the acute chest syndrome require cooperation between a hematologist and critical care specialist. Pregnant women also require

high-risk obstetric consultation and input from a hematologist. The general internist, pediatrician, or family physician can best address routine health maintenance and adequately manage the common complications (see the Box) associated with disease, such as most acute painful episodes and outpatient pain management.

Diagnosis and Evaluation... Sickled cells are nearly always seen in the blood of
patients with sickle cell anemia and HbS0-thalassemia but are less common in other genotypes. In adults, their numbers remain nearly the same over time and cannot be used as an indication of an acute sickle cell event. Exercise restrictions on carriers of the sickle cell trait need not differ from those used to forestall the ill effects of exercise in the general population.

CLINICAL BOTTOM LINE

Treatment and Management

18. 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;353:276978. [PMID:16382063] 19. Hulbert ML, Scothorn DJ, Panepinto JA, et al. Exchange blood transfusion compared with simple transfusion for first overt stroke is associated with a lower risk of subsequent stroke: a retrospective cohort study of 137 children with sickle cell anemia. J Pediatr. 2006;149:710-2. [PMID:17095350] 20. Atkins RC, Walters MC. Haematopoietic cell transplantation in the treatment of sickle cell disease. Expert Opin Biol Ther. 2003;3:1215-24. [PMID:14640947] 21. Hsieh MM, Kang EM, Fitzhugh CD, et al. Allogeneic hematopoietic stem-cell transplantation for sickle cell disease. N Engl J Med. 2009;361:230917. [PMID:20007560]

Few controlled clinical trials of treatment of the complications of sickle cell disease are available; trials that are available focus on sickle cell anemia (and usually include patients with HbS0-thalassemia and sickle cell anemia-thalassemia). No controlled trials of HbSC disease treatment have been published. The following questions are unanswered by clinical trials: How should the acute chest syndrome be managed? Can preoperative transfusion occasionally be avoided? Do angiotensin-converting enzyme (ACE) inhibitors delay sickle nephropathy? How is priapism best managed? How aggressively should blood pressure be lowered to decrease the chance of stroke? Treatment of these and most other complications are guided by expert opinion and reports of uncontrolled case series. Three treatment approaches have efficacy for many of the complications of sickle cell anemia: hydroxyurea, blood transfusion, and stem cell transplantation. Hydroxyurea treatment is underutilized, transfusions are often used inappropriately, and transplantation is rare. Trials comparing these treatments have not been done.

What drugs should be considered for the primary treatment of sickle cell anemia? Treatment for sickle cell disease is evolving. Many clinical trials of new agents are in progress, but new drugs are not yet available for treatment. Much can be done to promote better heath of individual patients, including good nutrition, avoidance of temperature extremes and dehydration, and genetic counseling. Hydroxyurea is the sole drug approved by the U.S. Food and Drug Administration for primary treatment of sickle cell anemia and is beneficial in most patients who strictly adhere to therapy.
A randomized, controlled clinical trial established the efficacy and safety of short-term use of hydroxyurea in adult sickle cell anemia. In a 9-year follow-up of this trial, mortality seemed to be reduced and this reduction was related to increased HbF levels and to a decrease in the acute chest syndrome and painful episodes. The benefits of hydroxyurea in adults are outlined in the Box: Benefits of Hydroxyurea in Sickle Cell Anemia. Follow-up for a total of 17.5 years continued to show reduced mortality in persons having received long-term hydroxyurea therapy (911). Most deaths occurred in patients who never took hydroxyurea or who took it

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for less than 5 years. Many other trials of hydroxyurea in patients of diverse ages support the use of this agent but are usually uncontrolled (12, 13).

Untreated sickle cell anemia is associated with high mortality, even in individuals with so-called mild disease. A compelling case can be made for giving hydroxyurea to most adults with sickle cell anemia and HbS0-thalassemia (14). Results of pediatric studies strongly argue for beginning this drug early in life, before irreversible vasculopathy and organ damage develop (15, 16). Long-term side effects of hydroxyurea started in young childhood are unknown. What is the role of blood transfusion in sickle cell disease? Simple transfusions to reduce HbS levels require only peripheral venous access, are rapidly available, and have a lower potential for alloimmunization but a greater chance of causing hyperviscosity. HbS levels are also reduced more gradually. Exchange transfusions usually take more time to initiate, require more complicated venous access, have a higher potential for alloimmunization and a lower risk for hyperviscosity, but more rapidly reduce HbS levels. When transfusions are urgent, simple transfusion can be done much more rapidly than exchange transfusion. Repeated transfusions of any type are associated with the serious complications of iron overload, alloimmunization, and transmission of infectious agents. Transfusions are not indicated to manage a routine painful crisis.
Preoperative transfusion

Exchange transfusions were associated with a higher incidence of alloimmunization (17). A control group receiving no transfusions was not included. A reasonable approach is to recommend simple transfusion to a hemoglobin level of 10 g/dL in all patients with sickle cell disease having intraabdominal and thoracic surgery, tonsillectomy, and other procedures requiring general anesthesia with a moderate to high risk. Minor elective procedures in children might be done without preoperative transfusions.
Transfusion in stroke

Benefits of Hydroxyurea in Sickle Cell Anemia

Reduced incidence of acute painful events and the acute chest syndrome Mortality reduced 40% Less hemolysis (improved anemia) Fewer hospitalizations Reduced medical costs Improved physical capacity

When patients with sickle cell disease should receive a transfusion is seldom informed by clinical trials. A trial of preoperative transfusions that randomized patients to receive either a simple transfusion to a hemoglobin level of 10 g/dL or an exchange transfusion aimed at reducing HbS levels to 30% showed that both practices successfully reduced (but did not eliminate) postoperative complications.

When acute nonhemorrhagic stroke has occurred, exchange transfusion is preferable to simple transfusion because it rapidly decreases the percentage of sickle cells. In a retrospective analysis (18), children receiving simple transfusion as an initial treatment had a 5-fold greater relative risk for a second stroke during follow-up than those receiving exchange transfusion. In patients not receiving transfusion, the risk for recurrent stroke is as high as 70% but is only about 10% in patients maintained at HbS levels of less than 30% by long-term transfusion therapy. This level can be allowed to increase to approximately 50% after several years at a level of 30% or less, with no added risk for recurrent stroke. Although chronic transfusion therapy is effective in decreasing the rate of recurrent infarctive stroke in children, this has not been proven to be an effective measure in patients who have their first stroke in adulthood; many strokes in adult sickle cell anemia are hemorrhagic where there is no evidence that transfusions are useful. Prophylactic blood transfusion can prevent a stroke in children who are identified to be at high risk by increased cerebral blood flow velocity estimated by transcranial Doppler flow studies (3). How long transfusions should be continued in at-risk patients is unknown. After 30 months or more of follow-up and normalization of cerebral flow rates,

22. Quinn CT, Rogers ZR, McCavit TL, Buchanan GR. Improved survival of children and adolescents with sickle cell disease. Blood. 2010;115:3447-52. [PMID: 20194891] 23. Vichinsky EP, Neumayr LD, Gold JI, et al; Neuropsychological Dysfunction and Neuroimaging Adult Sickle Cell Anemia Study Group. Neuropsychological dysfunction and neuroimaging abnormalities in neurologically intact adults with sickle cell anemia. JAMA. 2010;303:1823-31. [PMID: 20460621] 24. Ballas SK. Pain management of sickle cell disease. Hematol Oncol Clin North Am. 2005;19:785802, v. [PMID:16214644] 25. Smith WR, Penberthy LT, Bovbjerg VE, et al. Daily assessment of pain in adults with sickle cell disease. Ann Intern Med. 2008;148:94-101. [PMID: 18195334] 26. Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med. 2000;342:1855-65. [PMID:10861320] 27. Vichinsky E, Williams R, Das M, et al. Pulmonary fat embolism: a distinct cause of severe acute chest syndrome in sickle cell anemia. Blood. 1994;83:3107-12. [PMID:8193347] 28. Gladwin MT, Sachdev V, Jison ML, et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med. 2004;350:88695. [PMID:14985486]

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patients who were initially at high risk were randomly assigned to continue or discontinue transfusions. When transfusions were stopped, high-risk flow rates redeveloped in more than a third of cases and 2 had a stroke; flow remained normal, and no strokes occurred when transfusions were continued (19). Measuring cerebral blood flow by means of Doppler studies has not been applied to adults, so prophylactic treatment of stroke is not possible.
Transfusion in the acute chest syndrome

no longer anemic and had long-term, stable engraftment sufficient to eliminate the phenotype of sickle cell disease. Acute or chronic graft-versus-host disease did not occur (21).

The pathogenic and clinical complexity of the acute chest syndrome coupled with its clinical acuity has thwarted development of clinical trials of transfusion practices. Expert clinicians often choose transfusion when oxygen saturation is low, multiple lobes are affected, fever and tachycardia are substantial, anemia is increasing, leukocytosis is marked, and platelet counts are falling. Whether the outcome using exchange transfusion is superior to simple transfusion is unknown; it seems reasonable to recommend exchange transfusion for the sickest patients. Patients without hypoxia who have only minor chest infiltrates, minimal fever, and small changes in blood counts might not need transfusions. What is the role of bone marrow transplantation in sickle cell anemia? The mortality rate of transplantation has been about 5%. Eighty-four percent of patients have event-free survival, and about 10% have rejection or disease recurrence. When transplantation is successful, the disease is cured, albeit with some price in transplant-related morbidity. Myeloablative stem cell transplantation has been largely limited to children younger than 16 years of age with severe disease (20).
Ten patients aged 16 to 45 years who received nonmyeloablative transplantation with mobilized peripheral blood stem cells from HLA-matched siblings were alive at a median follow-up of 30 months. Nine were

What are the features of sickle cell anemia over a patients lifetime? What are the major complications of sickle cell disease? The features of sickle cell anemia change throughout life. In the first decade, severe life-threatening infection, dactylitis, the acute chest syndrome, splenic sequestration, and stroke are the major clinical features. Pain is often the main problem of adolescence. If the worst of childhood and adolescent problems are survived or escaped, young adulthood can be a time of relative clinical quiescence, but sickle vasculopathy is likely to progress despite causing few symptoms, and some adults will continue to have serious complications (22). Chronic organ damage leading to pulmonary vasculopathy, deteriorating pulmonary function, renal failure, and late affects of prior cerebrovascular disease (including neurocognitive impairment) become paramount as the patient ages (23). Any patient can have nearly all known disease complications, or almost none, and die with a sudden acute problem like multiorgan failure. Some skip one or more phases of the disease but suffer intensely from others. How does pain manifest in sickle cell disease and how is it managed? Pain is the hallmark of sickle cell disease (24) (Box: Clinical Features of the Acute Painful Episode). Most troubling are the acute painful episodes that force the patient to seek medical care, but chronic pain, acute pain complicating chronic pain, and therapy-induced pain are also prevalent. Some patients seem never to be pain-free; rare patients do not report acute pain episodes. Pain is worsened by major psychosocial issues. In some patients it is difficult to distinguish among different pain entities. Pain can occur

anywhere, be localized to one or a few areas, be migratory, or be generalized. Back, chest, extremities, and joints are most often involved. Typical painful episodes last 5 to 10 days in adults but some seem to persist for weeks (25). The frequency of acute pain episodes varies within and among individuals from rare to several times a month. Approximately a third of patients have few pain episodes, 50% have occasional episodes, and 20% have weekly or monthly episodes. A few patients account for most patients with acute pain episodes. The frequency of pain episodes increases late in the second decade of life and decreases in frequency after the fourth decade. More than 3 episodes a year is associated with reduced life expectancy. Emotional stress, changes in temperature, wind, dehydration, infection, fatigue, and overexertion are often mentioned as precipitating events, but events preceding an episode of acute pain are often not identifiable. Physical examination and laboratory testing provide few clues to the existence of an acute pain episode; a compatible history is the sole diagnostic criteria. Sickle cells are always found in the blood and are not diagnostically useful. How should pain be managed? Most pain is successfully managed at home. Many patients can sense the beginning of a pain episode and find increasing fluid intake, rest, warm baths, heating pads, and massage useful. Nonopioid analgesics are also used, followed by oral opioids if needed. U.S. patients having pain episodes that require medical intervention are usually treated in the emergency departments where pain should be rapidly assessed, treatment with parenteral opioids initiated and effectiveness evaluated, and the dosage adjusted as needed. The principles of acute pain management are outlined in

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the Box: Principles of Acute Pain Management. Most patients know their response to pain and analgesics best, and it is wise to heed their input. Patients with frequent episodes are often tolerant of opioids and require very large doses. Therapy must be individualized. Patients should be treated with an around-the-clock fixed-dose opioid schedule, with rescue doses of 25% to 50% of the fixed dose for breakthrough pain. Increase the dose if pain is not adequately relieved by the fixed dose; if the duration of pain control is inadequate, decrease the interval between dosing. Patientcontrolled analgesia has been used effectively. Analgesic doses vary considerably among patients, and they should be monitored carefully for oversedation, hypoxia, and a low respiratory rate. As pain subsides, the dose should be tapered and oral analgesics started. Adjuvant therapies, including antihistamines and nonsteroidal anti-inflammatory drugs, are also important to maximize pain management and to treat complications of therapy. Urine output may exceed 2 L/day, and pain is often accompanied by reduced fluid intake and increased water losses, so increased fluid intake is usually essential. Administration of 5% dextrose in water and 0.25 to 0.5 normal saline should be used for initial fluid replacement. Hydration should not be excessive to avoid iatrogenic heart failure or electrolyte imbalance; the daily fluid intake should be approximately 3 to 5 L for adults and 100 to 150 mL/kg for children. Oxygen should be reserved for patients who are hypoxic or have acute respiratory distress. Morphine and hydromorphone are the most frequently used parenteral opioids. Meperidine should be avoided because its metabolites cause central nervous system excitation. Oral opioids, transcutaneous fentanyl, and nonsteroidal analgesics are useful for

moderate pain and can be given with parenteral opioids in the hospital and for outpatient treatment. Long-term opioid use is common and is a major problem. Regular opioid use induces physiologic tolerance that reduces efficacy and the therapeutic index. Treatment of acute pain episodes can become increasingly difficult if a patient has a high level of tolerance. Interruption of regular opioid use can lead to withdrawal syndromes characterized by pain, often at the sites of sickle cell pain and accompanied by other symptoms that are often interpreted as acute pain. How are episodes requiring further treatment and continuously increased use and dose of opioids managed? Once the decision is made to initiate long-term opiate therapy, it is generally recommended that such therapy be based on a well-documented evaluation and treatment plan and that it be closely monitored (25) (Box: Causes of Persistent Severe Pain). Neuropathic pain can result from frequently recurring acute pain, nerve entrapment syndromes, neuronal ischemic damage, consequences of undertreated chronic pain, and complications of therapy. Chronic pain is challenging for patients and their care providers. Assessment includes defining the cause of the pain, determining pain intensity and effect on functioning and quality of life, and successful and unsuccessful coping strategies. Bone infarction, osteopenia and vertebral collapse, and osteonecrosis of the femoral and humeral heads are common causes of chronic pain. The causes of the intractable chronic pain seen in a minority of patients are unknown. Central sensitization from recurrent and perhaps undertreated pain leads to allodynia and hyperalgesia. Osteonecrosis of the hip, because of pain and loss of joint function, can dominate the clinical manifestation of

Clinical Features of the Acute Painful Episode

Most common complication: some patients always in pain; others rarely in pain Most pain is managed at home with oral analgesics Cause unclear: unrelated to new sickling and blood film is not helpful Pain distribution varies Physical findings limited Duration variable Frequent episodes are associated with a poor prognosis Directly related to packed cell volume; indirectly related to HbF

Principles of Acute Pain Management

Know and believe the patient Know the disease Know the pharmacology of analgesics Consider nonpharmacologic therapy Educate the patient Treat with short-acting parenteral opioids: morphine, hydromorphone, fentanyl Assess the patient Choose an analgesic: type, dose, route, patient-controlled anesthesia vs. bolus dosing Titrate drug to maximum effect Adjuvants: antidepressants, nonsteroidal anti-inflammatory drugs, antihistamines Manage side effects Give maintenance IV fluids Adjust dose and drug for tolerance and rotation Taper IV drug Switch to oral agents

Causes of Persistent Severe Pain

Progressive tissue damage Inadequate treatment Tolerance Hyperalgesia Changes at receptors Maladaptive behavior

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sickle cell anemia. Presenting with pain in and around the affected joint, at times with spasm of the surrounding musculature, hip disease can also present acutely and mimic septic arthritis or synovitis. By age 35 years, half of all persons with sickle cell anemia have evidence of hip and shoulder osteo-necrosis on magnetic resonance imaging (MRI). Osteonecrosis in sickle cell disease follows an inexorable path that ends with joint failure. Conservative treatment does not alter the progression of sickle osteonecrosis. As pain becomes intolerable and poorly responsive to oral analgesics, joint function can be lost; joint replacement is often needed. A common decision facing the physician is whether to hospitalize a patient having an acute painful episode. This decision should be made with the patient on the basis of his or her experience with home management and the response in the emergency department to parenteral opioids. Patients with the acute chest syndrome should always be hospitalized for treatment and follow-up. The critical decision when the acute chest syndrome is present is whether the patient should be admitted to the intensive care unit (ICU). Patients with hypoxia, respiratory distress, high fever, and tachycardia with laboratory findings divergent from baseline, such as marked leukocytosis, thrombocytopenia, or severe anemia, are often admitted to the ICU. How common is the acute chest syndrome in sickle cell disease, how does it manifest, how is it managed, and what are the current morbidity and mortality? Characterized by fever, chest pain, cough, and lung infiltrates, this sometimes-lethal complication affects more than half of all patients with sickle cell disease and is the second most common reason for hospitalization. The cause is multifactorial and includes infarction, pulmonary infection, atelectasis,

embolism (including necrotic bone marrow emboli), and in situ thrombosis. It is a frequent postoperative complication even when patients receive a transfusion before surgery. Fat embolism from necrotic bone marrow is a common cause of the most severe acute chest events, during which hemoglobin and platelet levels decrease and leukocyte count increases (26, 27). Extensive fat embolization causes an adult respiratory distresslike syndrome, in which maintaining adequate oxygenation is difficult and multiorgan failure with central nervous system disease, including lethargy progressing to coma, renal failure, hepatic failure, rhabdomyolysis, severe anemia, thrombocytopenia, and marked leukocytosis, develops. The acute chest syndrome is most common but least severe in young children, in whom it is often secondary to infection; mortality in adults is higher than it is in children. Regardless of the cause, which usually is not apparent, the acute chest syndrome is managed through transfusions, antibiotics, hydration with careful avoidance of overhydration, respiratory therapy with bronchodilators, incentive spirometry, and maintenance of tissue oxygenation. Oxygen is used when the patient is hypoxic or tachypneic and has signs of respiratory distress. Opioid use should balance pain relief with the danger of respiratory suppression. Although the acute chest syndrome is fatal in fewer than 10% of cases, a few patients have a rapidly deteriorating course. These persons quickly develop respiratory distress, increased oxygen requirements, and extensive pulmonary opacification with effusion and edema and can develop multiorgan failure. These individuals require admission to the ICU and often mechanical ventilation. Excessive intravenous hydration and opioids can contribute to development of an acute respiratory distresslike syndrome,

but it is equally likely that the triggering pulmonary eventfor example, fat embolizationwill elicit an uncontrolled inflammatory reaction that is refractory to the usual treatment. The acute chest syndrome probably does not contribute to the pulmonary vasculopathy of the disease but might result in altered pulmonary function. Aside from pain and acute chest syndromes, what other conditions complicate sickle cell anemia?
Pulmonary vasculopathy and pulmonary function

Pulmonary disease is a major cause of morbidity and mortality in adults with sickle cell disease. Much attention has been focused on echocardiographic abnormalities suggestive of pulmonary hypertension, which are common and associated with a poor prognosis. The initial test for screening and diagnosis is echocardiography, which allows for assessment of right and left ventricular size and function as well as estimation of the pulmonary artery systolic pressure via measurement of the TRV. This measurement is 2.5 m/sec or greater in approximately 30% of adults with sickle cell anemia and is associated with a 20% to 50% likelihood of dying within 2 years of detection (28). The high mortality rate associated with increased TRV might reflect the severity of the underlying sickle vasculopathy. In contrast to pulmonary arterial hypertension of other causes, pulmonary hypertension in sickle cell disease is hemodynamically mild to moderate, with pulmonary artery systolic pressures in the range of 35 to 50 mm Hg, and often increased pulmonary capillary wedge pressure, usually related to diastolic dysfunction of the left ventricle. Right heart catheterization is required for diagnosis of pulmonary arterial hypertension (PAH), which is found in only 5% to 10% of patients with an elevated TRV (5). This prevalence is actually quite high, similar to what is observed in systemic sclerosisassociated PAH and higher than that observed in association with HIV infection; portal

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hypertension; and the extremely rare, idiopathic PAH. The clinical significance of PAH in sickle cell disease is being defined and refined. Therefore, exactly how an increased TRV should be managed is unclear. If treatment seems to be necessary because of symptoms or hemodynamics, some experts would optimize transfusions and hydroxyurea therapy, even though the usual HbF levels achieved with hydroxyurea treatment do not seem to protect against this complication In this authors opinion, other complications of sickle cell disease, such as iron overload, HIV infection, hypoxemia (especially nocturnal hypoxemia), relative systemic hypertension, and thromboembolic disease, should be effectively managed before turning to therapies directed more specifically to PAH. Based on the value of anticoagulation in idiopathic PAH, anticoagulation with warfarin might be considered if a specific contraindication does not exist. For patients with PAH confirmed by right heart catheterization, pulmonary vasodilator therapy can be considered on a case-by-case basis. The prognostic value associated with increased TRV suggests that adults with sickle cell disease should have echocardiographic screening every 1 to 3 years. Symptomatic individuals should have an elevated TRV confirmed by right heart catheterization. Following optimization of sickle cell disease therapy, treatment specifically for PAH should be chosen in conjunction with a pulmonologist or cardiologist with experience managing this condition, as evidence-based approaches to this treatment in sickle cell disease are unavailable. Pulmonary function tests were abnormal in about 90% of adults with decreased total lung capacity and DLCO. Asthma and bronchial hyperactivity were more than twice as common in patients with sickle cell

disease than in controls. Asthma was also associated with a near doubling of the incidence of the acute chest syndrome and a 2-fold increase in mortality; it has also been associated with stroke in children (29).
Infection

Infection is the major cause of mortality and morbidity in young children, and the most common offending agent is Streptococcus pneumoniae. In adults, gram-negative organisms acquired via the urinary, respiratory, and gastrointestinal tract become more common and indwelling venous access devices become a common locus of infection.
Anemia

leukocytosis. Progressive renal failure, a consequence of aging in many patients, is also accompanied by worsening anemia that can be symptomatic and require chronic transfusions or erythropoietin to restore hemoglobin levels to prerenal-failure levels. Acute anemic episodes can result from the sudden trapping of red cells in the sinuses of an enlarging spleen (or liver) and can be lifethreatening. Aplastic crises or transient erythroid aplasia is usually caused by infection with parvovirus B19. It is typified by worsening anemia and reticulucytopenia, and patients require transfusion support unti the infection clears in 5 to 10 days.
Retinopathy

Most patients with sickle cell anemia have a moderate degree of stable anemia and a steady-state packed cell volume (PCV) between 25 and 30. Patients with HbSC disease and HbS+-thalassemia are usually less anemic than those with sickle cell anemia. Many patients with HbSC disease or HbS+-thalassemia with high levels of HbA, especially adult men, have nearly normal PCV. High PCV is not necessarily good because it affects blood viscosity. Patients with the most severe hemolysis have the highest steady-state LDH level, assuming that liver disease and other confounding elements that might affect LDH are absent. Individuals with the highest amounts of intravascular hemolysis have higher systolic blood pressure and a higher prevalence of leg ulcers, priapism, and increased TRV or N-terminal probrain natriuretic protein levels. They have less osteonecrosis and painful episodes. High hemolytic rates were also a risk factor for early death (30). Hemoglobin levels remain stable except for minor decreases during hospitalizations for acute pain episodes and the acute chest syndrome. Sometimes the decrease is more substantial, especially when an event is accompanied by a systemic inflammatory response with fever and

Patients with HbSC have a higher incidence of proliferative retinopathy, perhaps because of increased blood viscosity, although early loss of the peripheral retinal circulation in sickle cell anemia might prevent later development of proliferative vascular lesions.
Leg ulcers

Small superficial ulcers around the malleoli usually heal spontaneously with rest and careful local hygiene. At times, leg ulcers are huge, deep, exceedingly painful, disabling, and defy all simple and many complex therapeutic measures. All patients, especially those who have had leg ulcers, should be urged to protect their legs with support hose, avoid activities that cause swelling (such as prolonged standing), and use local lubricants that might help prevent excessive skin dryness and cracking. Control of local inflammation and infection ensuring a clean granulating surface for reepithelialization remains the mainstay of treatment.
Priapism

Sickle cell anemia is a leading cause of priapism (31). Recurrent attacks can last for several hours, although discomfort is usually tolerable. Major episodes of priapism can last for days

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and be very painful; it can cause irreversible corporal damage. No evidence for the benefits or risks of the various treatments for priapism exists. Recent uncontrolled studies have used sildenafil (32).
Renal disease

Renal complications are a common cause of morbidity and mortality, and renal failure has increased along with patient survival. Early elements of sickle cell renal disease include glomerular hyperfiltration, increased proximal tubular function, and hematuria. Subsequently, reduced concentrating ability, focal segmental glomerulosclerosis with proteinuria, papillary necrosis, impaired urine acidification and potassium secretion, and reduced glomerular filtration can develop. Survival time for patients with sickle cell anemia after diagnosis of renal failure was 4 years even when receiving dialysis, and the median age at the time of death was 27 years. Casecontrol analysis showed that ineffective erythropoiesis with increasingly severe anemia, hypertension, proteinuria, nephrotic syndrome, and microscopic hematuria were significant predictors of chronic renal failure. Albuminuria is a sensitive marker of glomerular damage and precedes development of overt renal insufficiency. Non-steroidal anti-inflammatory drugs that inhibit production of prosta-glandins can reduce glomerular filtration rate and might best be avoided in older persons with signs of incipient renal failure.
Digestive system disease

intra- and extrahepatic cholestasis, viral hepatitis, cirrhosis, and hypoxia and by combinations of infarction, erythrocyte sequestration, and iron overload. Sickle hepatopathy, hepatic crisis, and the right upper quadrant syndrome of sickle cell disease have been variously defined. Syndromes of benign intrahepatic cholestasis and acute hepatic sequestration occur.
Neurocognitive dysfunction

Electrocardiograms often show nonspecific abnormalities. Is pregnancy more complicated in women with sickle cell disease? Any approved form of contraception is acceptable, and pregnancy is not contraindicated. Most pregnancies can be successfully managed without regular transfusions. Multiple-birth pregnancies seem to benefit from transfusion. Pyelonephritis, pregnancy-induced hypertension, caesarian section, and obstetric complications are more common in women with sickle cell anemia than in controls. Prenatal testing should establish the hemoglobin phenotype and HbF level by high-performance liquid chromatography; blood counts; serum chemistries; hepatitis A, B, C, and HIV testing; urinalysis; urine culture; rubella antibody titer; and serum ferritin. All patients should have their red cell phenotype recorded and alloantibodies identified so that if transfusion is neededs, phenotypically matched blood can be used. Folic acid should be taken at a dose of 1 mg/day. Are patients with sickle cell disease at particularly high risk during surgery? Surgery and anesthesia are safe but not complication-free. The major issue in preoperative management is the question of blood transfusion, as discussed above. Preoperative preparation should also include hydration and optimization of pulmonary status. After surgery, rapid mobilization, incentive spirometry and bronchodilators, and close monitoring of oxygen saturation might help prevent the acute chest syndrome, and special vigilance should be directed toward its detection. How should end organ damage be monitored, treated, and prevented? Patients who are stable should be seen every 4 to 6 months, depending on treatment regimen and

Neurologically normal adults without a history of stroke or abnormal MRI had neuropsychological tests and MRI. Forty percent had abnormal scans, and mean IQ scores were below average (33). Memory, reading, and math performance were also decreased. Hemoglobin concentration was positively associated with IQ. These findings suggest that even neurologically normal adults can be neurocognitively impaired and might explain some of the unusual behaviors seen in some adults and attributed to poor adjustment and other nonorganic psychological problems. As patients with sickle cell disease live longer, what new health issues are emerging? Most clinics now see patients in the sixth and seventh decades of life (34). This is probably a result of better use of transfusions and hydroxyurea therapy and higher standards of supportive care. In the United States, the median age of death is the fifth decade (35). Cardiomegaly and heart murmurs often raise the question of whether congestive heart failure is present, but contractility is usually normal and overt congestive heart failure is uncommon. Hypertension can cause ventricular hypertrophy and heart failure and might contribute to sickle nephropathy and renal failure. Chest pain is very common, often leading to patients being told they have had a heart attack, but myocardial infarction is unusual.

Biliary tract disease and parenchymal liver disease are serious complications that affect the digestive system. Abdominal pain is frequent and can result from cholelithiasis or cholecystitis, intra-abdominal vasoocclusive disease, or intra-abdominal pathology apart from sickle cell anemia. Hyperbilirubinemia due to hemolysis is associated with a high prevalence of gallstones. Hepatomegaly is present in most patients and is contributed to by

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disease acuity. Blood counts are done, and renal and liver function are monitored at that time. In adults, it is reasonable to have periodic visits to an ophthalmologist for evaluation of sickle retinopathy, especially patients with HbSC

disease in whom this entity is far more common. Baseline and periodic estimation of TRV as an indicator of possible pulmonary hypertension and widespread vasculopathy and baseline pulmonary function testing are also useful.

Treatment and Management... Sickle cell disease has protean manifestations, and optimum care consists of direct drug therapy with hydroxyurea as well as prompt diagnosis and treatment of complications.

CLINICAL BOTTOM LINE

What should patients be taught about preventing disease complications? Patients often feel that they can sense the beginning of an acute pain episode and use the measures mentioned above to arrest their development; these are very individualized. Cold and windy conditions have been associated with painful episodes. The importance of avoiding extremes of temperature and maintaining good hydration should be stressed. The lower legs should be protected from trauma to avoid leg ulcers, and skin should be well-moisturized. Regular medical follow-up is paramount for prevention. What should patients be taught about prenatal screening and management of pregnancy? The availability of prenatal screening and its implications should be discussed with the family, preferably during planning but certainly in the first weeks of pregnancy. Pregnancies should be managed in a high-risk obstetrics clinic in consultation with a hematologist. Are there national support groups for patients with sickle cell disease? The Sickle Cell Disease Association of America (www.sicklecelldisease .org/) has local chapters that are a good source for discovering local support groups

Patient Education

Patient Education... Patients should be encouraged to learn to recognize the particular signs that signal onset of an acute crisis and to have regular medical follow-up from a primary care provider who has access to the expertise of a sickle cell center.

CLINICAL BOTTOM LINE

What measures do U.S. stakeholders use to evaluate the quality of care for patients with sickle cell disease? Many measurements have been used to gauge quality of care but none are universally applied. Some measures are selfhospital discharges, clinical pathways, treatment in multidisciplinary clinics, use of transcranial Doppler flow studies, and prophylactic penicillin in children and hydroxyurea. What do professional organizations recommend regarding care of patients with sickle cell disease? Many professional organizations have published guidelines for

Practice Improvement

29. Boyd JH, Macklin EA, Strunk RC, DeBaun MR. Asthma is associated with acute chest syndrome and pain in children with sickle cell anemia. Blood. 2006;108:2923-7. [PMID:16690969] 30. Taylor JG 6th, Nolan VG, Mendelsohn L, Kato GJ, Gladwin MT, Steinberg MH. Chronic hyper-hemolysis in sickle cell anemia: association of vascular complications and mortality with less frequent vasoocclusive pain. PLoS One. 2008;3:e2095. [PMID:18461136] 31. Rogers ZR. Priapism in sickle cell disease. Hematol Oncol Clin North Am. 2005;19:917-28, viii. [PMID:16214652] 32. Burnett AL, Bivalacqua TJ, Champion HC, Musicki B. Longterm oral phosphodiesterase 5 inhibitor therapy alleviates recurrent priapism. Urology. 2006;67:1043-8. [PMID:16698365] 33. Vichinsky EP, Neumayr LD, Gold JI, et al. Neuropsychological dysfunction and neuroimaging abnormalities in neurologically intact adults with sickle cell anemia. JAMA. 2010;303:1823-31. [PMID:20460621] 34. Quinn CT, Rogers ZR, McCavit TL, Buchanan GR. Improved survival of children and adolescents with sickle cell disease. Blood. 2010;115:3447-52. [PMID:20194891] 35. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994;330:1639-44. [PMID:7993409]

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management and follow-up of individuals with sickle cell disease. New quality of care indicators for children with sickle cell disease have been released (http://www.ncbi.nlm.nih .gov/pubmed/21844055). Another source for several guidelines is www.gfmer.ch/Guidelines/Anemia _and_hemoglobinopathies/Sickle _cell_anemia.htm/. Are there guidelines for transitioning care from pediatric to adult settings? Many experienced centers have established clinics to ease the

transition from pediatric to adult care. Flexibility is key, because each individual will adjust at a different rate. A reasonable curriculum for such a clinic can be found at www .childrenshospital.vanderbilt.org/ interior.php?mid=6755.

Practice Improvement... Clinical care programs for patients with sickle cell anemia should follow specific national guidelines and should be organized to provide an appropriate transition of care from pediatrics to internal medicine.

CLINICAL BOTTOM LINE

In the Clinic

PIER Module
http://pier.acponline.org PIER module on sickle cell anemia from the American College of Physicians.

Tool Kit
Sickle Cell Disease

Patient Information
www.acponline.org/fcgi/pierpi.pl?module=d905 Patient information material that appears on the next page for duplication and distribution to patients. www.nlm.nih.gov/medlineplus/sicklecellanemia.html www.nlm.nih.gov/medlineplus/ency/article/000527.htm www.nlm.nih.gov/medlineplus/spanish/ency/article/000527.htm Information on sickle cell anemia from National Institutes of Healths MedlinePLUS, including handouts in English and Spanish. http://scinfo.org/world-wide-resources/americans-with -disabilities-act Resources on sickle cell anemia, including Americans with Disabilities Act information, from the Sickle Cell Information Center. www.nhlbi.nih.gov/health/dci/Diseases/Sca/SCA_WhatIs.html Information on sickle cell anemia, in question -and-answer format, from the National Heart, Lung, and Blood Institute.

Clinical Guidelines
http://www.ncbi.nlm.nih.gov/pubmed/21844055 New quality-of-care indicators for children with sickle cell disease. http://consensus.nih.gov/2008/sicklecellstatement.htm Consensus development conference statement on hydroxyurea treatment for sickle cell disease, from the National Institutes of Health, released in 2008.

Diagnostic Tests and Criteria

www.uspreventiveservicestaskforce.org/uspstf/uspshemo.htm U.S. Preventive Services Task Force published a recommendation in 2008 that all newborns should be screened for sickle cell disease.

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THINGS YOU SHOULD KNOW ABOUT SICKLE CELL ANEMIA

What is sickle cell anemia?
Sickle cell anemia is an inherited blood disorder. Red blood cells are crescent- or sickle-shaped, rigid, and sticky and dont last as long as normal, round, flexible ones. A person with the disorder lacks enough healthy red blood cells to carry a full supply of oxygen throughout the body.

In the Clinic Annals of Internal Medicine

Who gets sickle cell anemia?

Sickle cell anemia occurs when a child inherits a defective form of the hemoglobin gene that causes sickle cell anemia from both parents and is more common among people of African, Mediterranean, Middle Eastern, or Indian ancestry. .

What is sickle cell crisis?

Sickle cell crisis is sudden pain occurring throughout the body. The pain can affect bones, joints, the lungs, and the abdomen. The crisis occurs when sickled red blood cells stick together and block blood flow. For some people with sickle cell anemia, a crisis occurs less than once a year; for others it occurs monthly, or more often. Repeated crises over time can damage kidneys, lungs, bones, eyes, heart, and liver.

How is it diagnosed?

Your doctor will order a blood test that checks for hemoglobin S, which is the defective form of hemoglobin underlying sickle cell anemia. The test is now routinely performed on newborn babies at the hospital. Diagnosis can be made before birth using amniotic fluid or tissue from the placenta.

What are common symptoms and complications?

Chronic fatigue from anemia. Pain, swelling, organ damage, and stroke if cells accumulate and block blood flow. Frequent infections if the spleen, an organ that fights infection, is damaged. Chest pain, fever, and difficulty breathing, which are caused by a lung infection or by sickle cells blocking blood vessels in the lungs. Yellowing skin and eyes (jaundice), if the liver is overwhelmed by the rapid breakdown of red blood cells.

How is sickle cell anemia treated?

For More Information

http://familydoctor.org/online/famdocen/home/common/blood/550.html

Tips for preventing sickle cell crisis from the American Academy of Family Physicians.
http://www.nlm.nih.gov/medlineplus/sicklecellanemia.html

Information on recent developments in sickle cell research from the National Institutes of Health.
www.cdc.gov/ncbddd/sicklecell/healthyliving-emer-guide.html

Information on red flags and when to call a doctor, from the Centers for Disease Control and Prevention.
www.nhlbi.nih.gov/health/dci/Diseases/bmsct/bmsct_whatis.html

Information on bone marrow and stem cell transplantation from the National Heart, Lung, and Blood Institute.

Patient Information

Folic acid supplements and adequate fluids. Pain relief, including prescription painkillers if needed. Hydroxyurea, a chemotherapy agent, to prevent pain episodes in severe sickle cell anemia. Blood transfusions to treat anemia, relieve acute pain, or prevent stroke or other emergencies. Antibiotics and vaccines to prevent infections. In some cases, bone marrow or stem cell transplantation can cure the disease.

CME Questions

1. A 15-year-old female African American is evaluated in the hospital after admission 5 days ago with acute right hemispheric stroke. Medical history is significant for sickle cell disease complicated by multiple episodes of the acute chest syndrome. Current medications are hydroxyurea and folic acid. On physical examination, temperature is 37.5C (99.5F), blood pressure is 166/92 mm Hg, pulse rate is 112/min and regular, and respiration rate is 18/min. The cardiopulmonary examination is unremarkable. There are no carotid bruits. Right upper and lower extremity weakness and aphasia are noted on neurologic examination. Laboratory studies indicate a hemoglobin level of 10.1 g/dL (101 g/L). An MRI shows an acute infarction in the territory of the right middle cerebral artery. In addition to aspirin, which of the following is the most appropriate secondary prevention of stroke in this patient?

fixed splitting of S2 with a palpable P2, and a systolic murmur at the lower left sternal border that increases with respiration. The lungs are clear. Examination of the lower extremities shows 2+ edema bilaterally. The chest radiograph reveals enlargement of the central pulmonary arteries with clear lung fields. Echocardiography discloses a normal left ventricular ejection fraction, right ventricular enlargement and hypertrophy, right atrial enlargement, tricuspid regurgitation, and paradoxical bulging of the septum into the left ventricle during systole. Which of the following is the most likely cause of this patients findings?

Which of the following medications is contraindicated in this patient?

A. Oxycodone B. Acetaminophen C. Inactivated influenza vaccine D. Folic acid E. Hydroxyurea

4. A 14-year-old girl with sickle cell disease is brought to the emergency department because of a typical vaso-occlusive crisis. Although intravenous fluids, supplemental oxygen, and narcotic analgesics are administered, the crisis does not abate, and she is hospitalized. On physical examination on admission, her temperature is 39.1C (102.4F), pulse rate is 130/min, respiration rate is 20/min, and blood pressure is 110/60 mm Hg. She has diffuse bone and abdominal pain that is most severe in the area of her right hip. A radiograph of the right hip reveals evidence of bony destruction in the femur at the level of the metaphysis. Two sets of blood cultures are obtained, and the patient is sent for urgent CT-guided bone biopsy to obtain appropriate cultures and histopathologic samples. While awaiting culture results, which of the following is most appropriate?

A. Constrictive pericarditis B. Giant cell myocarditis C. Pulmonary hypertension D. Hypertrophic cardiomyopathy

3. A 24-year-old black woman with sickle cell disease is admitted to the hospital with a typical painful crisis involving pain in the back and legs. The patient is 12 weeks pregnant with her first child. She also has dysuria and urinary frequency and urgency. Her only medication is folic acid. On physical examination, the patient is in obvious discomfort. Temperature is 38.7C (101.8F), blood pressure is 130/64 mm Hg, pulse rate is 112/min, and respiration rate is 22/min. Arterial oxygen saturation on ambient air is 95%. The patient has a gravid uterus appropriate for gestation. Her lungs are clear, and there is no costovertebralangle tenderness. Laboratory studies show the following: hemoglobin , 7.2 g/dL (72 g/L); leukocyte count , 13,200/L (13.2 109/L); and urinalysis , positive for leukocyte esterase. A chest radiograph is normal. She is treated with intravenous hydration, amoxicillin, and analgesics and does well and is now ready for discharge.

A. Clopidogrel B. Dipyridamole C. Angiotensin-converting enzyme inhibitor D. Monthly erythrocyte transfusions

2. A 46-year-old black man is evaluated in the emergency department with swelling of the feet and ankles and a 2-month history of worsening dyspnea. The patient has homozygous sickle cell disease and a history of lower extremity ulcers and episodes of acute chest syndrome. Current medications are hydroxyurea and folic acid. He has no known drug or other allergies. On physical examination, temperature is normal, blood pressure is 145/85 mm Hg, pulse rate is 98/min, and respiration rate is 28/min; body mass index is 22. Jugular venous pressure is elevated and is associated with large a and v waves. On cardiac examination, there is a heave,

A. Begin cefazolin B. Begin vancomycin C. Begin vancomycin plus ceftriaxone D. Begin trimethoprimsulfamethoxazole E. Await culture results before beginning antimicrobial therapy

Questions are largely from the ACPs Medical Knowledge Self-Assessment Program (MKSAP, accessed at http://www.acponline.org/products_services/mksap/15/?pr31). Go to www.annals.org/intheclinic/ to complete the quiz and earn up to 1.5 CME credits, or to purchase the complete MKSAP program.

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