Opportunities to Improve Outcomes in Sickle Cell Disease

SATYEN R. MEHTA; ARABA AFENYI-ANNAN; PATRICIA J. BYRNS; RICHARD LOTTENBERG

SATYEN R. MEHTA, M.D., ARABA AFENYI-ANNAN, M.D., M.P.H., PATRICIA J. BYRNS, M.D., AND RICHARD LOTTENBERG, M.D.

Am Fam Physician. 2006;74(2):303-310

Patient information: See related handout on sickle cell disease, written by the authors of this article.

Author disclosure: Nothing to disclose.

Sickle cell disease represents a spectrum of inherited hemoglobin disorders. The pathophysiology involves abnormalities not just in red blood cells but also vascular endothelium, white blood cell function, coagulation, and inflammatory response. Known sequelae of sickle cell disease include invasive infections, painful episodes, acute chest syndrome, strokes, and chronic pulmonary hypertension. Preventive strategies that decrease the risk of infection are the routine use of daily antibiotics until five years of age, immunization of children with the 7-valent pneumococcal conjugate vaccine in addition to the 23-valent polysaccharide pneumococcal vaccine, annual influenza vaccination after six months of age, and meningococcal vaccination after two years of age. A significant advance in stroke prevention is the use of transcranial Doppler ultrasonography to identify asymptomatic, at-risk children who should be considered for chronic blood transfusions. Chronic transfusion therapy for primary or secondary stroke prevention requires careful surveillance for iron overload and chelation therapy. Patients with chest pain, fever, or respiratory symptoms and new pulmonary infiltrates require aggressive medical management for acute chest syndrome. Pain management still represents an important area for aggressive treatment using sickle cell disease–specific guidelines. Newer treatments include hydroxyurea therapy to decrease the frequency of painful episodes and associated comorbidities, and hematopoietic cell transplantation for a limited subset of patients. Family physicians play a crucial role in instituting evidence-based preventive care strategies, initiating timely treatment of acute illness, recognizing life-threatening episodes, and providing a medical home for multidisciplinary management.

In just one generation, the average survival of patients with sickle cell anemia (hemoglobin SS) has increased from 14 years to nearly 50 years.^1,2 Sickle cell disease includes a number of genotypes (Figures 1 and 2) and a wide range of associated phenotypes characterized by chronic hemolysis, tissue infarction, and painful episodes (Table 1). Sickle cell disease was once thought to involve solely the polymerization of hemoglobin S, but it is now known that vaso-occlusion also involves leukocytes, activated vascular endothelium, altered nitric oxide metabolism, hypercoagulability, and ischemia-reperfusion injury.^3,4 Advances in the understanding of sickle cell disease patho-physiology have led to new opportunities to improve patient care. This article provides an update of prevention and management strategies to modify the progression of disease and enable primary care physicians to better recognize complications that require the input of subspecialists.

Clinical recommendation	Evidence rating	References
Screening
Primary care physicians should screen infants and children for hemoglobinopathies if no records are available.	B	⁵, ⁶
Children with sickle cell disease should be screened with transcranial Doppler ultrasonography starting at two years of age (frequency of rescreening has not been established).	C	¹⁸, ¹⁹
Recommended frequency of comprehensive medical examination should be guided by ongoing consultation with hematologists specializing in sickle cell disease. Physicians should screen for asymptomatic renal, pulmonary, and liver disease, and for drug-related complications for specific therapies.	C	¹⁰, ²⁸
Patients with sickle cell disease should receive periodic retinal screening beginning at 10 years of age.	C	¹⁰
Vaccines for patients with sickle cell disease*
In patients six months and older, influenza vaccine should be given annually.	C	¹⁴
The 7-valent pneumococcal conjugate vaccine (Prevnar) should be administered as for children without sickle cell disease.	B	¹²
The 23-valent polysaccharide pneumococcal vaccine should be administered if two years or older, with another dose at three to five years (if patient is 10 years or younger) or five years (if patient is older than 10 years) after the first dose.	B	¹²
Meningococcal vaccine is recommended for patients two years and older with sickle cell disease.	C	¹⁵
Interventions
Infants and children with sickle cell disease should receive prophylactic daily penicillin V potassium (Veetids) starting by two months of age. Dosages change at three years of age.	A	⁷, ⁸
Antibiotic prophylaxis may be stopped after five years of age for patients without a history of invasive pneumococcal infection or splenectomy.	B	⁹
Hydroxyurea should be considered for adults and older adolescents with sickle cell anemia who experience three or more moderate to severe vasoocclusive painful episodes per year.	A	³⁴
Hydroxyurea should be considered for adults with a history of severe or recurrent acute chest syndrome or symptomatic anemia.	C	²⁸
Hospital-based treatment of acute painful episodes
Optimize pain management using opioids based on American Pain Society algorithms.	C	²⁷
Intravenous fluids should be hypotonic and, after correction for volume depletion, limited to maintenance requirements.	C	²⁹
Incentive spirometry should be used during waking hours.	A	³⁰
Monitor oxygen saturation and avoid oversedation.	C	²⁹

Hemoglobinopathy	Clinical manifestations	Hb (g per dL)	Hb S (%)	Hb A (%)	Hb A₂(%)	Hb F (%)
Sickle cell trait (carrier)	Asymptomatic*	Normal	40	60	< 3.5	0
Sickle cell disease (common variants)
Hb SS (sickle cell anemia)	Usually marked †	6 to 8	> 90	0	< 3.5	< 10
Hb S beta°-thalassemia	Marked to moderate †	7 to 9	> 80	0	> 3.5	< 20
Hb S beta⁺-thalassemia	Mild to moderate †	9 to 12	> 60	10 to 30	> 3.5	< 20
Hb SC	Mild to moderate †	10 to 15	50	0	‡	0

Integrating New Preventive Care Strategies

Neonatal diagnostic screening for hemoglobinopathies, timely institution of family education, and antibiotic prophylaxis remain among the most successful preventive care strategies. Not all states have universal screening, and screening may not have been available for children born in another country; therefore, if no record is available, physicians should consider screening new patients.^5,6 Regarding antibiotic prophylaxis, infants and children with sickle cell disease should receive prophylactic daily penicillin V potassium (Veetids) starting by two months of age (intramuscular penicillin G benzathine [Bicillin L-A] given every three weeks can be substituted).^7,8 Antibiotic prophylaxis can be stopped safely at five years of age for patients without a history of invasive pneumococcal infection or splenectomy.⁹ Primary care physicians can improve outcomes by augmenting vaccinations based on risk, screening children to identify those who will benefit from stroke prophylaxis, and screening for pulmonary hypertension. There is a need for periodic comprehensive medical examinations that include assessment of liver, pulmonary, and renal functions. The frequency of examinations should be guided by consultation with hematologists specializing in sickle cell disease. Ophthalmologic examination should be performed periodically after the age of 10.¹⁰

SPECIAL RECOMMENDATIONS FOR IMMUNIZATION

Children with sickle cell disease should receive all routine childhood immunizations. The new 7-valent pneumococcal conjugate vaccine (PCV; Prevnar) decreases the incidence of invasive pneumococcal infection in children younger than two years and should be given to infants with sickle cell disease on the same schedule as other children.^11,12 However, because children with sickle cell disease remain susceptible to life-threatening pneumococcal infections, they should receive the 23-valent polysaccharide pneumococcal vaccine (PPV) if two years or older; and, if the patient is 10 years or younger, revaccination should be considered three to five years later.^12,13 These immunizations do not obviate the need for penicillin prophylaxis, which should continue until five years of age.⁸ Other recommendations include annual influenza immunization for patients six months and older and meningococcal vaccination for patients two years and older.^14,15

ADDRESSING THE HIGH INCIDENCE OF STROKE

Neurologic complications are relatively common in children and adults with sickle cell disease.¹⁶ In fact, 17 percent of asymptomatic children with hemoglobin SS disease have structural changes on magnetic resonance imaging consistent with “silent” infarctions.¹⁷ Occlusive strokes are attributed to persistent sickling and probable endothelial proliferation, leading to narrowing of cerebral blood vessels. Fortunately, primary prevention of childhood stroke is now possible because effective screening and treatment exist.

Screening with specialized transcranial Doppler ultrasonography is recommended for asymptomatic children with sickle cell disease beginning at two years of age to identify those with an abnormal transcranial blood-flow velocity (TBV).^18,19 Children with TBV of 200 cm per second or more are at a particularly high risk of stroke.²⁰ In a multicenter clinical trial¹⁸ using this TBV criterion for enrollment, 16.4 percent of children receiving standard care had a stroke during a mean follow-up of 18 months; chronic transfusions reduced the incidence of stroke to 1.6 percent. Furthermore, the most recent data indicate that patients revert back to high-risk status if the transfusions are discontinued.²¹ Transfusion therapy should be considered for children at increased risk of stroke.¹⁹

Recognition of incipient stroke is critical for all children and adults. Symptoms may be as subtle as behavioral changes or a prolonged headache, or even may be part of an uncomplicated painful episode. Prompt brain imaging studies (computed tomography and magnetic resonance angiography) should be performed, and consultation with neurology and hematology subspecialists should be obtained if there is any suspicion for stroke.

EARLY RECOGNITION OF PULMONARY HYPERTENSION

The prevalence of pulmonary hypertension in adults with sickle cell disease may be as high as 30 percent.^22,23 Children may be affected as well. Transthoracic Doppler echocardiography with attention to the tricuspid regurgitant jet can identify a subset of patients at increased risk of death (odds ratio, 10.1).²⁴ Thus, a high index of suspicion is warranted when evaluating patients with sickle cell disease who have unexplained dyspnea, hypoxemia, physical examination findings such as increased intensity of the second heart sound, or right ventricular enlargement on chest radiography. Many experts now advocate periodic screening of all adults with sickle cell disease. Echocardiography should be performed when the patient is not acutely ill; those who have abnormal study results should then be referred to a hematologist. Treatment of pulmonary hypertension associated with hemolytic anemias is an area of active investigation at many referral centers.

Management of Acute Complications

PAINFUL EPISODES

Painful episodes occur when sickled erythrocytes cause microvascular occlusion that results in tissue inflammation and ischemia. Comprehensive approaches to ambulatory and inpatient pain management have been addressed in a number of publications, including two with useful algorithms.^25,26 In addition, monographs published by the American Pain Society²⁷ and the National Institutes of Health²⁸ are of particular benefit in establishing clinical pathways for hospital-based pain management in patients with sickle cell disease.

Recommendations include the timely use of opioid medications for moderate to severe pain and avoidance of meperidine (Demerol). Oxygen supplementation is not needed unless hypoxemia is present. Close monitoring of oxygen saturation and respiratory status, with particular attention to avoid excessive sedation, is necessary.²⁹ Ancillary measures to reduce the incidence of complications include the use of frequent incentive spirometry while the patient is awake and avoidance of fluid overload by limiting overall intake to 1.0 to 1.5 times maintenance needs.^29,30

ACUTE CHEST SYNDROME

Acute chest syndrome, characterized by respiratory or chest symptoms, fever, and a new pulmonary infiltrate on chest radiography, has many etiologies (Table 2).²⁹ Acute chest syndrome may complicate any painful episode or other acute medical condition in a patient with sickle cell disease. For example, 30 percent of all patients with hemoglobin SS disease will have one episode of acute chest syndrome; one half of these patients will have recurrent episodes.³¹ Because survival is improved with aggressive treatment, urgent consultation with a hematologist or pulmonologist is advised. For persistent hypoxemia or respiratory deterioration in the face of conservative measures, transfusion of red blood cells is indicated.²⁹

Symptoms
New onset of chest pain
Fever
Wheezing
Dyspnea or tachypnea
Cough
Chest radiography findings
New pulmonary infiltrate
Clinical setting
As the presenting condition without apparent precipitating factors
During painful episodes
During neurologic events
Active respiratory infection (e.g., bronchitis, pneumonia)
Postoperative
Etiology
Fat embolism
Infection
	Bacteria (including mycoplasma, legionella, chlamydia)
	Mixed infection
	Viruses
Pulmonary infarction
Laboratory testing
Blood and sputum cultures
Continuous or interval pulse oximetry
Daily complete blood count and serum chemistry panel
Arterial blood gas measurement for change in oxygen saturation
Pre- and post-transfusion hemoglobin S concentration (hemoglobin electrophoresis)
Treatment
Supplemental oxygen for Po₂ below 80 mm Hg or oxygen saturation below 95 percent
Incentive spirometry while awake
Broad-spectrum antibiotic therapy to include coverage for atypical organisms
Fluid management with attention to cardiopulmonary status, daily intake/output analysis, and daily weight
Aggressive pain management with respiratory monitoring and avoidance of oversedation
Bronchodilator therapy if reactive airway disease
Transfusion therapy for hypoxemia or clinical deterioration occurring despite the above interventions

MULTIPLE ORGAN FAILURE SYNDROME

This life-threatening complication involves the acute development of severe dysfunction in at least two of three major organs (kidney, liver, or lung) during a painful episode. Fever, a drop in hemoglobin level, decreasing platelet count, rhabdomyolysis, and mental status changes are all associated with the onset of multi-organ failure. This rare complication is one of the most challenging for even the most experienced sickle cell disease expert. Prompt consultation with a hematologist is advised because emergent exchange transfusion can be lifesaving.³²

Strategies to Modify Disease Outcomes

HYDROXYUREA THERAPY

Hydroxyurea increases hemoglobin F levels, improves red cell deformability and hydration, and reduces red cell adhesion to vascular endothelium.³³ In a randomized placebo-controlled trial, adults with hemoglobin SS receiving hydroxyurea had significant reductions in painful crises (from 4.5 to 2.5 per year), the incidence of acute chest syndrome, and the frequency of transfusions.³⁴ Follow-up data at nine years from an observational study³⁵ of patients on hydroxyurea showed not only continuing clinical response but also a 40 percent reduction in mortality. Thus, adults and older adolescents with sickle cell disease who experience frequent painful episodes or who have a history of severe or recurrent acute chest syndrome, other vaso-occlusive episodes, or symptomatic anemia should be considered candidates for hydroxyurea therapy.²⁸ Table 3 shows the types of assessment, baseline work-up, and laboratory studies required by the consulting hematologist for treatment initiation.

Baseline laboratory evaluation
CBC with WBC differential and reticulocyte count
Hemoglobin F measurement
Renal and liver function tests
Pregnancy test
Counseling
Women and men taking hydroxyurea should use contraception.
Dosage modification is required to optimize opportunity for clinical response and avoid complications from myelotoxicity.
Monitoring
Blood counts at frequent intervals early in therapy and when dosage changes
Periodic renal and liver function tests
Hemoglobin F levels and red blood cell MCV values to detect a biologic response (i.e., an increase in these parameters)
Patient compliance
Dosage escalation end points
Reduction in sickle cell pain frequency and/or severity
A treatment period of six months may be needed to assess response in patients who continue to have symptoms.
	If lack of clinical response: (1) myelotoxicity that defines the maximum tolerated dosage for the patientor (2) maximum dosage of 35 mg per kg per day

Comanagement of chronic hydroxyurea therapy requires the family physician and office personnel to be familiar with the side effects of the medication and to be able to provide close follow-up during therapy. Clinical studies of hydroxyurea treatment in infants and children show promising results as well, but this therapy is not approved by the U.S. Food and Drug Administration for this population, and longer-term follow-up is necessary to ascertain the risk of adverse effects.³⁶

ACUTE AND CHRONIC TRANSFUSION THERAPY

Family physicians should request consultation with a hematologist and a blood bank physician when considering transfusions for patients with sickle cell disease. In general, transfusions should not be used for uncomplicated, acute, painful episodes; minor surgical procedures; chronic anemia without symptoms; or uncomplicated pregnancies. As described earlier, transfusion therapy often is of great benefit. The risks of transfusion therapy, whether acute or chronic, need to be managed carefully to avoid adverse events, because the end points for transfusion in patients with sickle cell disease differ from the end points in other patients.

Exchange transfusion may be necessary as an alternative to simple transfusion to avoid hyperviscosity and volume overload. The blood bank should be notified immediately of the possible need for transfusion because patients with sickle cell disease have special needs for matching red blood cell antigens, and they are at increased risk for transfusion reactions because of sensitization by previous transfusions. Delayed hemolytic transfusion reactions may be difficult to recognize because the symptoms may overlap those of a severe painful episode. Finally, patients who are receiving chronic transfusions must be monitored for iron overload that ultimately will require chelation therapy. Table 4^{18,28,29,32,37–45} provides some major indications for transfusion therapy.

Episodic transfusions
Progressive symptoms of acute chest syndrome
Multi-organ failure syndrome
Acute splenic or hepatic sequestration
Major surgical procedures/general anesthesia; tonsillectomy and adenoidectomy should not be considered low-risk procedures.*
Acute management of stroke
Symptomatic anemia
Pregnant patients: medical and obstetric complications
Chronic transfusions
Primary stroke prevention for at-risk children as identified by transcranial Doppler ultrasonography
Prevention of stroke recurrence
Chronic heart failure
Pulmonary hypertension
Prevention of recurrent splenic sequestration

HEMATOPOIETIC CELL TRANSPLANTATION

The only curative treatment for patients with sickle cell disease is allogeneic hematopoietic cell transplantation (HCT).⁴⁶ There are published reports⁴⁷ on more than 200 patients with hemoglobin SS disease who were treated with HCT. The disease-free survival rate achieved with HCT ranges from 85 to 90 percent. However, transplant-related mortality is 5 to 10 percent, mainly because of graft-versus-host disease and infection.

Because of even higher mortality in older persons, trials to date typically have included only patients 16 years or younger who have a human leukocyte-antigen–matched sibling and have already had a sickle cell disease–related complication such as stroke, acute chest syndrome, mild chronic lung disease, or red cell alloimmunization resulting from long-term transfusion. Current barriers to the widespread use of transplantation include the lack of human leukocyte-antigen–identical donors and the associated toxicity of current protocols.

Life-Cycle Needs of Patients with Sickle Cell Disease

Family physicians, in collaboration with a sickle cell disease subspecialist, play a critical role in ensuring that patients receive optimal preventive, acute, and chronic care. In addition to the clinical management addressed above, there are specific life-cycle issues that deserve attention. Infants and children clearly benefit from health care supervision provided by a comprehensive sickle cell center. A recent study⁴⁸ shows that more than 85 percent of children with sickle cell disease who are involved with such a program survive to 18 years of age. The increase in survival of children has led to a burgeoning adult population with sickle cell disease. Young adulthood signals not only the need for greater responsibility in their health care but also potential problems with adjusting to adult-oriented health care settings. The American Academy of Family Physicians has endorsed a consensus statement⁴⁹ on the need for coordinated health care programs to address these issues during transition to adulthood.

Adult patients require periodic evaluations by a sickle cell disease expert. Additionally, pregnancy represents a time when comanagement with hematology and high-risk obstetric subspecialists can decrease morbidity for mother and child. Because the older patient with sickle cell disease often faces additional problems caused by chronic organ damage, there is a need for subspecialists to be actively involved in ongoing health care. Table 5 provides a list of helpful Internet resources for obtaining updated information on sickle cell disease.

Centers for Disease Control and Prevention Vaccination/Immunization Schedules
	Web site:http://www.cdc.gov/nip/recs/child-schedule.htm (children) orhttp://www.cdc.gov/nip/recs/adult-schedule.htm (adults)
Comprehensive Sickle Cell Centers
	Web site:http://www.rhofed.com/sickle
Emory University Sickle Cell Information Center
	Web site:http://www.scinfo.org/
NIH Clinical Trials Information
	Web site:http://www.clinicaltrials.gov
NIH/NHLBI The Management of Sickle Cell Disease
	Web site:http://www.nhlbi.nih.gov/health/prof/blood/sickle/index.htm or http://www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf
Sickle Cell Disease in Children and Adolescents: Diagnosis, Guidelines for Comprehensive Care, and Protocols for Management of Acute and Chronic Complications (Texas Department of State Health Services)
	Web site:http://www.dshs.state.tx.us/newborn/sickle.shtm
Sickle Cell Disease Association of America
	Web site:http://www.sicklecelldisease.org

Diggs LM. Anatomic lesions in sickle cell disease. In: Abramson HA, Bertles JF, Wethers DL, eds. Sickle Cell Disease: Diagnosis, Management, Education, and Research. St. Louis, Mo.: Mosby, 1973:189–229.

Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994;330:1639-44.

Steinberg MH. Management of sickle cell disease. N Engl J Med. 1999;340:1021-30.

Ataga KI, Orringer EP. Hypercoagulability in sickle cell disease: a curious paradox. Am J Med. 2003;115:721-8.

Lees CM, Davies S, Dezateux C. Neonatal screening for sickle cell disease. Cochrane Database Syst Rev. 2000;2:CD001913.

Vichinsky E, Hurst D, Earles A, Kleman K, Lubin B. Newborn screening for sickle cell disease: effect on mortality. Pediatrics. 1988;81:749-55.

Gaston MH, Verter JI, Woods G, Pegelow C, Kelleher J, Presbury G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial. N Engl J Med. 1986;314:1593-9.

Riddington C, Owusu-Ofori S. Prophylactic antibiotics for preventing pneumococcal infection in children with sickle cell disease. Cochrane Database Syst Rev. 2002;3:CD003427.

Falletta JM, Woods GM, Verter JI, Buchanan GR, Pegelow CH, Iyer RV, et al. Discontinuing penicillin prophylaxis in children with sickle cell anemia. Prophylactic Penicillin Study II. .J

American Academy of Pediatrics. Health supervision for children with sickle cell disease. Pediatrics. 2002;109:526-35.

Kaplan SL, Mason EO, Wald ER, Schutze GE, Bradley JS, Tan TQ, et al. Decrease of invasive pneumococcal infections in children among 8 children’s hospitals in the United States after the introduction of the 7-valent pneumococcal conjugate vaccine. Pediatrics. 2004;113(3 pt 1):443-9.

Advisory Committee on Immunization Practices. Preventing pneumococcal disease among infants and young children. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2000;49(RR-9):1-35.

Davies EG, Riddington C, Lottenberg R, Dower N. Pneumococcal vaccines for sickle cell disease. Cochrane Database Syst Rev. 2004;1:CD003885.

Harper SA, Fukuda K, Uyeki TM, Cox NJ, Bridges CB. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP) [Published correction appears in MMWR Recomm Rep 2004;53:743]. MMWR Recomm Rep. 2004;53(RR-6):1-40.

Bilukha OO, Rosenstein N for the National Center for Infectious Diseases, Centers for Disease Control and Prevention (CDC). Prevention and control of meningococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2005;54(RR-7):1-21.

Powars D, Wilson B, Imbus C, Pegelow C, Allen J. The natural history of stroke in sickle cell disease. Am J Med. 1978;65:461-71.

Armstrong FD, Thompson RJ , Wang W, Zimmerman R, Pegelow CH, Miller S, et al. Cognitive functioning and brain magnetic resonance imaging in children with sickle cell disease. Neuropsychology Committee of the Cooperative Study of Sickle Cell Disease. Pediatrics. 1996;97(6 pt 1):864-70.

Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, 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.

Goldstein LB, Adams R, Alberts MJ, Appel LJ, Brass LM, Bushnell CD, et al. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council. Stroke. 2006;37:1583-633.

Adams RJ, McKie VC, Carl EM, Nichols FT, Perry R, Brock K, et al. Long-term stroke risk in children with sickle cell disease screened with transcranial Doppler. Ann Neurol. 1997;42:699-704.

Adams RJ, Brambilla D for the 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;353:2769-78.

Sutton LL, Castro O, Cross DJ, Spencer JE, Lewis JF. Pulmonary hypertension in sickle cell disease. Am J Cardiol. 1994;74:626-8.

Simmons BE, Santhanam V, Castaner A, Rao KR, Sachdev N, Cooper R. Sickle cell heart disease. Two-dimensional echo and Doppler ultrasonographic findings in the hearts of adult patients with sickle cell anemia. Arch Intern Med. 1988;148:1526-8.

Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med. 2004;350:886-95.

Preboth M. Management of pain in sickle cell disease. Am Fam Physician. 2000;61:1544-90..

Yale SH, Nagib N, Guthrie T. Approach to the vaso-occlusive crisis in adults with sickle cell disease [Published correction appears in Am Fam Physician 2001;64:220]. Am Fam Physician. 2000;61:1349-56.

Benjamin LJ, Dampier CD, Jacox A, Odesina V, Pheonix D, Shapiro BS, et al. Guideline for the management of acute and chronic pain in sickle-cell disease. American Pain Society. APS Clinical Practice Series. 1999;1:xi.

National Institutes of Health. National Heart, Lung, and Blood Institute. The Management of Sickle Cell Disease. 4th ed. Bethesda, Md.: The Institute, 2002; NIH publication no. 02–2117.

Vichinsky EP, Neumayr LD, Earles AN, Williams R, Lennette ET, Dean D, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease [Published correction appears in N Engl J Med 2000;343:824]. N Engl J Med. 2000;342:1855-65.

Bellet PS, Kalinyak KA, Shukla R, Gelfand MJ, Rucknagel DL. Incentive spirometry to prevent acute pulmonary complications in sickle cell diseases. N Engl J Med. 1995;333:699-703.

Castro O, Brambilla DJ, Thorington B, Reindorf CA, Scott RB, Gillette P, et al. The acute chest syndrome in sickle cell disease: incidence and risk factors. Blood. 1994;84:643-9.

Hassell KL, Eckman JR, Lane PA. Acute multiorgan failure syndrome: a potentially catastrophic complication of severe sickle cell pain episodes. Am J Med. 1994;96:15562 :

Charache S. Mechanism of action of hydroxyurea in the management of sickle cell anemia in adults. Semin Hematol. 1997;34(3 suppl 3):15-21.

Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med. 1995;332:1317-22.

Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A, et al. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment [Published correction appears in JAMA 2003;290:756]. JAMA. 2003;289:1645-51.

Zimmerman SA, Schultz WH, Davis JS, Pickens CV, Mortier NA, Howard TA, et al. Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease. Blood. 2004;103:2039-45.

Emre U, Miller ST, Gutierez M, Steiner P, Rao SP, Rao M. Effect of transfusion in acute chest syndrome of sickle cell disease. J Pediatr. 1995;127:901-4.

Emond AM, Collis R, Darvill D, Higgs DR, Maude GH, Serjeant GR. Acute splenic sequestration in homozygous sickle cell disease: natural history and management. J Pediatr. 1985;107:201-6.

Vichinsky EP, Haberkern CM, Neumayr L, Earles AN, Black D, Koshy M, et al. A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. N Engl J Med. 1995;333:206-13.

Koshy M, Weiner SJ, Miller ST, Sleeper LA, Vichinsky E, Brown AK, et al. Surgery and anesthesia in sickle cell disease. Blood. 1995;86:3676-84.

Koshy M, Chisum D, Burd L, Orlina A, How H. Management of sickle cell anemia and pregnancy [Published correction appears in J Clin Apher 1992;7:221]. J Clin Apher. 1991;6:230-3.

Russell MO, Goldberg HI, Hodson A, Kim HC, Halus J, Reivich M, et al. Effect of transfusion therapy on arteriographic abnormalities and on recurrence of stroke in sickle cell disease. Blood. 1984;63:162-9.

Wang WC, Kovnar EH, Tonkin IL, Mulhern RK, Langston JW, Day SW, et al. High risk of recurrent stroke after discontinuance of five to twelve years of transfusion therapy in patients with sickle cell disease. J Pediatr. 1991;118:377-82.

Rao S, Gooden S. Splenic sequestration in sickle cell disease: role of transfusion therapy. Am J Pediatr Hematol Oncol. 1985;7:298-301.

Grover R, Wethers DL. Management of acute splenic sequestration crisis in sickle cell disease. J Assoc Acad Minor Phys. 1990;1:67-70.

Iannone R, Ohene-Frempong K, Fuchs EJ, Casella JF, Chen AR. Bone marrow transplantation for sickle cell anemia: progress and prospects. Pediatr Blood Cancer. 2005;44:436-40.

Walters MC. Stem cell therapy for sickle cell disease: transplantation and gene therapy. Hematology (Am Soc Hematol Educ Program). 2005:66-73.

Quinn CT, Rogers ZR, Buchanan GR. Survival of children with sickle cell disease. Blood. 2004;103:4023-7.

American Academy of Pediatrics; American Academy of Family Physicians; American College of Physicians-American Society of Internal Medicine. A consensus statement on health care transitions for young adults with special health care needs. Pediatrics. 2002;110(6 pt 2):1304-6.