Management of Sickle Cell Diseasein Primary Care

Robert Edward Wilson, BS1Lakshmanan Krishnamurti, MD2Deepak Kamat, MD, PhD3

Introduction

S ickle cell disease (SCD) is a

hereditary hemoglobinopa-thy that is manifested by

chronic hemolytic anemia and in-termittent occlusion of smallblood vessels leading to chronictissue ischemia, chronic organ

damage, and dysfunction. In theUnited States, approximately2000 infants affected by this disor-der are born each year.' Over thepast few decades, there has been a

significant decrease in the mor-

bidity and improvement in thelife expectancy of patients withSCD due to early detection as wellas effective and comprehensivetreatment of these patients.2 Thiscomprehensive care is providedby a multidisciplinary team con-

sisting of a primary care provider(PCP), hematologist-oncologist,and other subspecialists. This re-

view article outlines the role a

PCP can play in the comprehen-sive care of patients with SCD.

Pathophysiology andGenetics of Sickle CellDisease

Hemoglobin A is a tetramericprotein that is composed of two oxglobin chains and two P globinchains. In sickle cell anemia, a

point mutation on the globingene at position six, results in glu-

tamic acid substituting for valine.This single amino acid substitu-tion results in the development ofsickle cell hemoglobin (HgbS).This mutation is common in per-

sons with African, Mediterranean,Middle Eastern, Indian, Carib-bean, and Central and SouthAmerican ancestry and passed on

to the next generation in an auto-

Clin Pediatr. 2003;42:753-761

'Medical School, West Virginia University, Morgantown, West Virginia; 2Children's Hospital ofPittsburgh; 3Director, Institute of Medical Education, Children's Hospital of Michigan, Detroit,Ml 48201.

Reprint requests and correspondence to: Deepak Kamat, MD, PhD, Professor, Director,Institute of Medical Education, Children's Hospital of Michigan, Detroit, Ml 48201.

2003 Westminster Publications, Inc., 708 Glen Cove Avenue, Glen Head, NY 11545, U.S.A.

somal recessive manner.3 Individ-uals who are heterozygous for thismutation are carriers for sicklecell and have no disease manifes-tations. Individuals homozygousfor this mutation have SCD. Thefour most common genotypespresent within the United Statesare SCD (HbSS), sickle-hemoglo-bin C disease (HbSC), and twoforms of sickle/p-thalassemia(HbS3+ and HbS 0).4 Overall, pa-tients with HbSS and HbS fO-tha-lassemia have more severe clini-cal manifestations than thosewith other genotypes. However,there is unpredictable variabilityin clinical expression and severityof disease among the variousgenotypes.5

The clinical manifestations ofSCD are due to hemolysis andepisodic vascular occlusioncaused by polymerization and ag-

gregation of the HbS moleculesduring deoxygenation. Due tothis polymerization, the red bloodcells acquire a holly leaf or sickleshape. The sickled red blood cellbecomes rigid and less de-formable. Consequent to hemoly-sis, red blood cell survival may bereduced to as little as 20 days.There is increasing understand-ing of the role played by the inter-action of the red blood cell, thecells lining the endothelium, and

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Wilson, Krishnamurti, Kamat

platelets in the pathophysiologyof SCD. The increased expressionof adhesion molecules on the sur-

face of damaged red blood cells,endothelium, and platelets leadsto increased adhesiveness of thered blood cell, which maybe theinitiating factor for vasoocclu-sion.6 Chronic anemia, jaundice,predisposition to aplastic crisis,and delayed growth and develop-ment are consequences of hemol-ysis. The vaso-occlusive episodescause tissue ischemia as well as

acute and chronic organ damageand dysfunction. The common

clinical manifestations of SCD are

shown in Table 1.

Diagnosis of SickleCell Disease

SCD is now identified in mostinfants by routine neonatalscreening. Universal neonatalscreening for SCD is provided in44 states, the District of Colum-bia, Puerto Rico, and the VirginIslands.3 In the other six stateswhere the testing is not required,it is available upon request. Anyinfant who is considered high risk(African American, Mediter-ranean, Caribbean, Middle East-ern, Indian, and Central andSouth American ancestry) andwas not screened at birth shouldundergo hemoglobin elec-trophoresis. The blood sampleused for the screening test shouldalways be taken before any bloodtransfusions so that the transfusedhemoglobin does not interferewith the detection of HgbS.

The tests used for screeninginclude isoelectric focusing (IEF),high-performance liquid chro-matography (HPLC), and cellu-lose acetate electrophoresis. Ifany of these initial tests show ab-normal results, then one of theconfirmatory tests is performed.

The confirmatory test should bedone within 2 months so thatproper medical care can be initi-ated. Commonly used tests toconfirm the diagnosis of SCD are

electrophoresis, HPLC, immuno-logic assays, and DNA-based assays.7

Patient and FamilyEducation

The family and other care-

givers are critical for successfultreatment of the patient; thispoint should be emphasized atevery patient visit. Once the pa-

tient with SCD is identified, thePCP must thoroughly educate theparents or other caregivers aboutthe disorder. The PCP should ed-ucate the caregivers about the ge-

netics of SCD and offer carriertesting to the parents. The impor-tance of regular health mainte-

nance visits, as well as the need forurgent medical evaluation for anyfebrile illness (temperaturegreater than 38.5°C) or otheracute complication should bestressed. To ensure timely medicalevaluation for acute illness, thePCP must provide anticipatoryguidance to the caregivers aboutearly recognition and proper

medical evaluation of acute com-

plications. Parents should betaught the technique of palpationof spleen and educated for i)when to seek medical care ur-

gently if the child becomes ill andhas significant increase in the sizeof the spleen, ii) how to avoidvaso-occlusive complications andtreat pain, and iii) when to ad-minister prophylactic antibiotics.Educational materials and meth-ods should be matched to the lit-eracy level of the caregiver. In-structions should be provided on

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how to navigate the medical sys-

tem. Information about physicalfindings, laboratory values, andmedications should be retainedby the caregiver in case it isneeded in an emergency.4 At theappropriate age, the patient mustbe educated about the genetics ofSCD and issues related to contra-ception.' It is important that thecaregivers have access to emer-

gent medical care at a facility thatis geared to provide care to sicklecell patients and which preferablyhas specific information on theindividual patient.

The ultimate goal of the pa-

tient education is not only to pro-

vide information about proper

medical care for the disorder, butalso to assist these families in cop-

ing with the disorder so that thepatient and family may lead a fulland happy life.

Medical Management

Since the introduction ofpenicillin prophylaxis policies,newborn screening, new immu-

nizations, and comprehensivemedical care centers, the sur-

vival of young children withsickle cell disease has improved.8Comprehensive management ofSCD requires a team that com-

prises primary care physicians,

hematologists, nurses, health edu-cators, and medical social work-ers. Often emergency departmentphysicians, radiologists, anesthesi-ologists, surgeons, and criticalcare specialists also become in-volved. Communication betweenthese health care providers is crit-ical to the delivery of optimal care

for this group of patients. Care-givers help in this communicationby keeping the health care

providers informed of any

changes in symptoms, physicalfindings, laboratory results, and

medications. The routine care forthe patient should be handled bythe PCP, with periodic referrals tothe SCD specialist to provide com-plete patient evaluations and forthe treatment of life-threatening,acute complications. Completemedical care also includes peri-odic psychological evaluations todetermine how both the patientand the family are adapting to thechronic disorder. It is also the re-

sponsibility of the PCP to informthe patient and the family of sup-

port groups and other organiza-tions that are available for boththe patient and the family to helpthem cope with this chronic dis-order.

Health Care Maintenance

The patient with SCD must

undergo regular, scheduled med-ical evaluations throughouthis/her life so that the PCP can

review the course of the disease,document physical findings andlaboratory values, monitorgrowth and development, con-

tinue patient and caregiver edu-cation, and develop medical care

plans for the patient and providespecific information on sickle celldisease to the parents.3 Duringthe first 2 years of life, the patientshould be seen every 2 to 3months, preferably the visitsplanned to coincide with the im-munization schedule. After thesecond year, the patient should beseen at least every 6 months, un-

less the patient needs medicalevaluation sooner.3

Physical ExaminationThe examination findings of

patients with SCD are quite vari-able. Blood pressure is usuallylower in these patients comparedto that in healthy individuals;however, because elevated blood

pressure is associated with in-

creased risk for stroke in these pa-

tients, the blood pressure shouldbe monitored carefully in thesepatients.9 In many instances,jaun-dice associated with mild indirecthyprebilirubinemia is the firstphysical sign noted on examina-tion during the first few weeks oflife. While the spleen frequentlyundergoes autoinfarction in earlychildhood, it is not uncommon tofind an enlarged spleen in sicklecell patients. While it occurs mostoften in milder variants of SCDsuch as HgbSC, it may also be de-tected in younger or even olderchildren with HgbSS disease.Many of the patients with SCDhave a benign functional systolicmurmur due to anemia. Expan-sion of the marrow cavity, may

lead to skeletal changes such as

maxillary overgrowth and over-

bite. Patients should be advised toregularly see a dentist. Growthand development should be fol-lowed closely in children withSCD, and nutrition should be op-

timized. Children and parentsshould be counseled about poten-tial social problems related toshort stature and delayed sexualdevelopment, which greatly af-fects adolescents.

Laboratory EvaluationIt is essential that laboratory

evaluation be done on a regularbasis so that baseline values forthe patient are kept up to date.Complete blood cell count withdifferential, reticulocyte count,percentage of HgbS/HgbF, andrenal and liver function testsshould be checked regularly(Table 2).

Special StudiesPatients with SCD are at high

risk for damage to many vital or-

gans, including the brain andlungs. Therefore other laboratory

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studies are used for early detec-tion of organ damage and to pre-

vent further deterioration in theorgan function.

Lung function declines withage in patients with SCD; there-fore, the PCP should identifythose patients who need closermonitoring and management.Pulmonary function tests (PFT)are the gold standard for identify-ing any lung dysfunction. Patientswho have a history of recurrentacute chest episodes or low oxy-

gen saturation should have PFTsperformed regularly.4

Transcranial Doppler ultra-sonographies (TCD), magneticresonance imaging (MRI) with or

without angiography, and neu-ropsychometric (NPM) studieshave been used extensively toevaluate children with SCD.2These studies are essential be-cause they identify those patientswith an increased risk for stroke.TCD is used to help evaluateblood flow velocity through theinternal carotid artery; abnor-mally high velocities are associ-ated with an increased risk ofstroke.10-12 It is recommendedthat TCD screening for patientswith SCD should start at 2 years ofage. If the results are normal,

then the TCD is continued annu-

ally; however, patients who havequestionable results should haveTCD repeated every 4 months,while patients with abnormal re-

sults should have a repeat studywithin 2 to 4 weeks. Stroke pre-

vention strategies based on abnor-mal MRI have not been tested,but children with abnormal MRIor NPM studies could be evalu-ated more frequently and consid-ered for therapeutic measures.12

ImmunizationBecause splenic dysfunction

develops in patients with SCD atan early age, they are at increasedrisk for infections with encapsu-

lated bacteria, mainly with Strepto-coccus pneumoniae. Thus, all pa-

tients with SCD are required tohave the routine childhood im-munizations including immuniza-tion against pneumococci. Thevaccines available against pneu-

mococcus include the pneumo-

coccal-conjugated vaccine (PCV7, Prevnar) and the pneumococ-

cal polysaccharide vaccine(PPV23). Prevnar is recom-

mended by the American Acad-emy of Pediatrics (AAP) for chil-dren with SCD up to 59 months ofage.13 There is no reason why

older SCD patients should not re-

ceive the vaccine.4The 23-valent pneumococcal

polysaccharide vaccine (PPV23 or

23PS) can be used in childrenover the age of 2 years, along withPrevnar.14 A recommended im-munization schedule for preven-

tion of pneumococcal infectionsis described in Table 3, and a rec-

ommended schedule for catch-upimmunization for previously vac-

cinated children with sickle celldisease is described in Table 4.

Meningococcal vaccine is notroutinely recommended for pa-

tients with SCD in the UnitedStates. This is probably due to theinfrequency of these infections.However, if children live in or

travel to areas where there is a

higher prevalence of meningo-coccal infections, then theyshould be vaccinated. The AAP2000 Red book, however, recom-

mends meningococcal vaccine toall patients with SCD along withyearly influenza vaccine.13

Antibiotic ProphylaxisBecause of the increased risk

of pneumococcal infections, pa-

tients with SCD are also started onantibiotic prophylaxis in additionto immunization. The prophylac-

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Management of Sickle Cell Disease

tic therapy is essential for the well-being of the patient; this must beemphasized at every visit to pre-

vent noncompliance. These pa-

tients are administered penicillinVK 125 mg twice daily beginningby 2 months of age and when thechild becomes 3 years of age, thedosage is doubled to 250 mg twicedaily.'4 In young children, the rel-atively short shelf life (2 weeks)and unpalatability of penicillinsuspensions may be limitation.Amoxicillin can be substituted.Another alternative is an injec-tion of Bicillin, which is adminis-tered every 3 weeks. Penicillin pro-

phylaxis should be continued atleast until 5 years of age.14 If pa-

tients have had an episode ofpneu-mococcal sepsis, penicillin must becontinued lifelong. For patientswho are allergic to penicillin, ery-

thromycin ethyl succinate (20mg/kg divided into two doses) can

be used for prophylaxis.3

NutritionMothers of infants with SCD

are encouraged to breast feed, butmay use an iron-fortified formulaif they are unable to breast feed.Folic acid (1 mg orally) is givendaily to patients with chronic he-molysis, such as those with SCD, to

reduce the risk of bone marrow

aplasia. Reports of folate levelsamong SCD patients have beenmixed. While one recent studyfound that folate stores in childrenwith SCD not receiving folic acidsupplements are adequate,'5 an-

other found that more than half ofthe SCD subjects had inadequateintake of folate from food, and de-spite daily folate supplementation,15% had low RBC folate levels.'5'16Additional research is needed toexplore the effects of improved fo-late status, the need for folate sup-

plementation, and the relation-ship of folate, vitamin B12, andhomocysteine levels and the riskfor vascular damage and stroke inchildren with sickle cell disease. Inthe meanwhile, folate supplementis a relatively inexpensive, simple,and nontoxic intervention.

Management ofAcute Illness

Patients with SCD present withthe same acute symptoms as nor-

mal healthy children; namelyfever, cough, and abdominalpain. However, patients with SCDshould be evaluated and treatedimmediately because these couldbe symptoms of life-threatening

infections in these patients. Someof the acute complications ofSCDare briefly discussed below.

FeverSplenic dysfunction develops

in patients with SCD as early as 3months ofage who are therefore atincreased risk for pneumococcaland other encapsulated bacterialinfections, such as meningitis andsepsis.17 Therefore any child withSCD who presents with a fever ofgreater than 38.5°C and othersigns of infection (chills, lethargy,irritability, etc.) should be evalu-ated immediately. A completeblood cell (CBC) count and retic-ulocyte count, blood and cere-

brospinal fluid cultures (plusurine culture if urinary tract infec-

tion is suspected), and a chest radi-ograph should be ordered andbroad-spectrum antibiotics shouldbe started promptly. Because of itslong half-life, ceftriaxone is usuallychosen for selected cases in whichoutpatient management with closefollow-up may be appropriate.'8 Abacterial infection is not the onlyconcern when the patient presentswith fever; other acute complica-tions, such as aplastic crisis andsplenic sequestration, are alsocommonly associated with fever.

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PainThe hallmark clinical manifes-

tation of SCD is the acute vaso-oc-

clusive event, or painful episode.Episodes of severe pain in pa-

tients with SCD are both unpre-

dictable and common.19 Typically,the earliest symptom is dactylitis,or "hand-foot syndrome," andstarts before the patient turns 1

year of age. Other sites that maybe involved are the limbs, abdom-inal viscera, ribs, sternum, andskull. These episodes usually haveno identifiable etiology or precip-itating factors, but occasionallymay follow an acute illness.

Caregivers should be taughthow to recognize a painfulepisode, and then manage thepain of the patient so that mild-moderate pain can be controlledat home. Frequently, the pain can

be managed with oral analgesics,such as acetaminophen, non-

steroidal anti-inflammatory drugs

such as ibuprofen, and mild opi-oids such as codeine. If the pain isnot alleviated at home by thesemeasures, then the patient istriaged and evaluated immedi-ately. Parenteral opioids, such as

intravenous morphine, are indi-cated in episodes of severe, un-

controllable pain. Ketorolac hasbeen shown to be quite effective,and it can lessen the requirementfor intravenously administerednarcotics.20 Close observation ofthe patient is required, payingspecial attention for the develop-ment of other acute complica-tions, particularly acute chest syn-

drome.2' Major barriers toeffective management of pain are

clinicians' limited knowledge ofSCD, inadequate assessment ofpain, and concern about opioiduse. Opioid tolerance and physi-cal dependence must be distin-guished from addiction. Unwar-ranted fear of addiction is

common among patients andfamilies, as well as healthcareworkers. Clinicians should askabout pain and use the patient'sself-report as the primary source

of pain assessment. Most SCDpain can be managed well if careprovided with adequate attentionto pharmacology of opioids, pa-

tient response to treatment, andin the context of a comprehensivepsychosocial support. Hydrox-yurea can decrease the incidenceand severity of pain episodes by as

much as 50%.22-24 Preliminary re-

sults of studies examining the ef-fectiveness of hydroxyuea in chil-dren with SCD are promising.23,24

Acute Chest SyndromeAcute chest syndrome (ACS)

is an illness characterized by a

new pulmonary infiltrate identi-fied on chest radiograph, in addi-tion to other lower respiratorytract symptoms (fever >38.50C,

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cough, chest pain, dyspnea, andwheeze) and /or hypoxemia.25This syndrome can develop 2 to 3days after an episode ofvaso-occlu-sive pain, or may present along

with an acute infection. ACS may

also complicate general anesthesiaand surgery.26 The primary causes

are pulmonary infection, pul-monary infarct, and pulmonary fatembolism.25 Early recognition andaggressive treatment is critical be-cause the patient may rapidlyprogress to pulmonary failure anddeath. Because of this rapid clini-cal progression, the child with ACSshould be hospitalized and closelyobserved, often in a pediatric in-tensive care unit.3 Treatment con-

sists of oxygen, analgesics, broad-spectrum antibiotics (plus a

macrolide or quinolone must beincluded to cover the atypical bac-teria), and simple (or exchange)transfusions.

Aplastic CrisisAplastic crisis is a temporary

cessation of bone marrow activity,which results in an exacerbationof the patient's anemia. Thisacute complication is usually trig-gered by an infection that resultsin direct cytotoxicity to erythroidprecursors. Most cases of aplasticcrisis are caused by an infectionby the human parvovirus B19.4The characteristic rash of ery-

thema infectiosum is usually ab-sent in patients with aplastic crisis.The diagnosis of aplastic crisis ismade by comparing CBC andreticulocyte counts obtained dur-ing acute illness with the baselinevalues and the reticulocyte countis typically less than 1%.7 The di-agnosis is supported by an in-crease in parvovirus B19 IgM lev-els. Although many patientsrecover spontaneously, red bloodcell transfusions should be con-

sidered for those who becomesymptomatic and blood transfu-

sion is usually recommended inthe child whose hematocrit is20% to 25% below baseline.27However, if there is evidence forbone marrow recovery (deter-mined by an increased reticulo-cyte count), then transfusion maynot be required. The other treat-ment suggested for parvovirusinfection and acute aplasia is a

one-time dose of intravenous im-munoglobulin (IVIG) followed bydaily infusions of erythropoietin.Patients with SCD should be iso-lated from individuals affected byparvovirus B19.

Splenic SequestrationSplenic sequestration is an

acute complication characterizedby an acutely enlarging spleen,with a decrease in the hemoglo-bin level and a rise in the reticulo-cyte count.7 Severe cases progress

rapidly to shock and death andtherefore, immediate recognitionand treatment is essential. Oncesplenic sequestration is recog-

nized, the patient should betreated with red blood cell trans-fusion.28 These patients are rec-

ommended to undergo splenec-tomy shortly after the episode, or

be placed on a chronic transfu-sion program.4 Patients who havea life-threatening episode of acutesplenic sequestration crisis thatrequires transfusion supportshould have a splenectomyshortly after the event or beplaced on a chronic transfusionprogram. Splenectomy is not rec-

ommended for patients below 2years of age. Patients who have a

severe episode of ASSC and are

below 2 years of age should beplaced in a chronic transfusionprogram to keep Hgb S levels be-low 30% until a splenectomy can

be considered after 2 years of age.

Patients with chronic hyper-splenism also should be consid-ered for splenectomy.

StrokePatients with SCD have an in-

creased risk for stroke and nearly10% of patients with SCD havestrokes, with the peak incidencebetween 4 and 6 years of age. Astroke may present with a varietyof manifestations, such as dyspha-sia, hemiparesis, cranial nerve

palsy, severe headache, stupor,and coma.29 Patients with anyacute neurologic symptom otherthan mild headache need promptevaluation. Initial evaluationshould include a CBC count,reticulocyte count, and magneticresonance imaging (MRI) or

non-contrast-enhanced com-

puted tomography (CT); thenon-contrast-enhanced CT isused to rule out a hemorrhage.Once the diagnosis of stroke ismade, the patient is treated withan exchange transfusion andmonthly transfusions are themain treatment currently recom-mended for stroke.1229 Anticon-vulsants may be indicated for pa-tients who have seized, butprophylactic treatment is notrecommended.

PriapismPriapism is a sustained,

painful, and unwanted erectionthat is a common complication ofSCD.30 The mean age at which itoccurs is 12 years, and nearly 90%of males with SCD experience pri-apism by the age of 20. Priapism isclassified into two classes, de-pending on the timing of theepisode. If it lasts less than 3 hoursand resolves spontaneously, it isthe stuttering form; however, ifthe episode persists for more than3 hours, it is considered a severe

form, which requires immediatemedical attention and a urologicconsultation.31 If therapy is de-layed past 3 hours, there is an in-creased risk of fibrosis and impo-tence. The goal of therapy is to

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ease the pain, reduce the erectionand preserve future erectile func-tion.4 The patient should be givenIV hydration and parenteral anal-gesia, and if the episode persistsan exchange blood transfusion isalso considered, especially for pa-

tients with recurrent episodes. As-piration and irrigation of the cor-

pus cavernosum by an urologistshould also be considered if pri-apism persists.32 For patients whohave recurrent episodes, consid-eration should be given to pro-

phylactic medication, such as

pseudoephedrine, stilbestrol, or

leuprolide. These medicationsmay help, but at this time no dataare available from a large studywhich has studied the efficacy ofthese medications.

The PCP must educate andcounsel male patients about pri-apism. A recent study showed thatless than 10% of male patients whohad not had an episode ofpriapismknew that it is a complication ofSCD. These patients, as well as

their caregivers, should be taughtto seek medical attention as soon as

the episode develops. A full blad-der may induce an episode; thus,regular urination is essential forprevention. Prolonged sexual activ-ity may also trigger an episode, andshould be avoided.

Gallbladder DiseasePatients with SCD have an in-

creased risk for developing pig-mented gallstones due to chronichemolysis in SCD. The onset ofcholelithiasis begins by 4 years ofage, and increases in prevalencewith age. Pigmented gallstonesdevelop in roughly 30% of pa-

tients with SCD by the age of 18.If the patient has severe right-up-per quadrant pain, then ultra-sound is used to diagnose thepresence of gallstones. These pa-

tients should then undergo la-paroscopic cholecystectomy.

Conclusion

Sickle cell disease is a chronichemolytic disorder. The survivaland longevity of these patientshave increased significantly in re-

cent years due to early detectionand improvements in the treat-ment of complications. The PCPin collaboration with hematolo-gist plays an important role in thetreatment of these patients with a

chronic disorder. Patients requirecomprehensive care, anticipatoryguidance, and support. They maypresent with distressing or life-threatening symptoms and re-

quire timely evaluation and ap-

propriate care or consultation.Good communication is essentialbetween the caregiver, the PCP,and the hematologist for proper

management of patients withSCD.

REFERENCES1. Pass KA, Lane PA, Fernhoff PM, et al.

US newborn screening system guide-lines 11: follow-up of children, diag-nosis, management, and evaluation.Statement of the Council of RegionalNetworks for Genetic Services(CORN).JPediatr 2000;137:SI-46.

2. Lee A, Thomas P, Cupidore L, Ser-

jeant B, Serjeant G. Improved survivalin homozygous sickle cell disease:lessons from a cohort study. BMJ.1995;311:1600-1602.

3. Anonymous. Health supervision forchildren with sickle cell disease. Pedi-atrics. 2002;109:526-535.

4. Anonymous. The Management of SickleCell Disease. Bethesda, MD: NationalInstitutes of Health. National Heart,Lung, and Blood Institute. Division ofBlood Diseases and Resource; 2002.

5. Miller ST, Sleeper LA, Pegelow CH, et

al. Prediction of adverse outcomes inchildren with sickle cell disease.NEnglJMed. 2000;342:83-89.

6. Frenette PS. Sickle cell vaso-occlusion:multistep and multicellular paradigm.Curr Opin Hematol. 2002;9:101-106.

7. Anonymous. Sickle CellDisease: Screening,Diagnosis, Management, and Counselingin Newborns and Infants. Clinical prac-

tice guideline 6. Rockville, MD: ahcpr,phs, US Department of HHS; 1993.

8. Vichinsky EP. Comprehensive care insickle cell disease: its impact on mor-

bidity and mortality. Semin Hematol.1991;28:220-226.

9. Pegelow CH, Colangelo L, SteinbergM, et al. Natural history of blood pres-

sure in sickle cell disease: risks forstroke and death associated with rela-tive hypertension in sickle cell ane-

mia. AmJMed. 1997;102:171-177.10. Adams RJ, McKie VC, Carl EM, et al.

Long-term stroke risk in children withsickle cell disease screened with tran-

scranial Doppler. Ann Neurol.1997;42:699-704.

11. Adams RJ, McKie VC, Hsu L, et al. Pre-vention of a first stroke by transfusionsin children with sickle cell anemia andabnormal results on transcranialDoppler ultrasonography. N EnglJMed. 1998;339:5-11.

12. Adams RJ, Ohene-Frempong K, WangW. Sickle cell and the brain. Hematol-ogy. 2001:31-46.

13. American Academy of Pediatrics.Committee on Infectious Diseases.Policy statement: recommendationsfor the prevention of pneumococcalinfections, including the use of pneu-mococcal conjugate vaccine (Pre-vnar), pneumococcal polysaccharidevaccine, and antibiotic prophylaxis.Pediatrics. 2000;106:362-366.

14. Overturf GD. American Academy ofPediatrics. Committee on InfectiousDiseases. Technical report: preven-

tion of pneumococcal infections, in-cluding the use of pneumococcal con-

jugate and polysaccharide vaccinesand antibiotic prophylaxis. Pediatrics.2000;106:367-376.

15. Rodriguez-Cortes HM, GrienerJC, et

al. Plasma homocysteine levels and fo-late status in children with sickle cellanemia. J Pediatr Hematol Oncol.1999;21:219-223.

16. Kennedy TS, Fung EB, Kawchak DA,Zemel BS, Ohene-Frempong K,Stallings VA. Red blood cell folate andserum vitamin B12 status in childrenwith sickle cell disease. JPediatrHema-tol Oncol. 2001;23:165-169.

760 CLINICAL PEDIATRICSNOVEMBER/DECEMBER

2003760 CLINICAL PEDIATRICS NOVEMBER/DECEMBER 2003

Management of Sickle Cell Disease

17. Zarkowsky HS, Gallagher D, Gill FM,et al. Bacteremia in sickle hemoglo-binopathies. J Pediatr 1986;109:579-585.

18. Williams LL, Wilimas JA, Harris SC,Day SW, Dancy RM, Wang WC. Out-patient therapy with ceftriaxone andoral cefixime, for selected febrile chil-dren with sickle cell disease. J PediatrHematol Oncol. 1996;18:257-261.

19. Platt OS, Thorington BD, BrambillaDJ, et al. Pain in sickle cell disease.Rates and risk factors. N EnglJ Med.1991;325:11-16.

20. Anonymous. Guideline for the Manage-ment ofAcute and Chronic Pain in SickleCell Disease. APS clinical practiceguideline; no. 1. Glenview IL: Ameri-can Pain Society (APS), 1999.

21. Bellet PS, Kalinyak KA, Shukla R,Gelfand MJ, Rucknagel DL. Incentivespirometry to prevent acute pul-monary complications in sickle cell dis-eases. NEngIJ Med. 1995;333:699-703.

22. Steinberg MH. Management of sicklecell disease. NEnglJ Med. 1999;340:1021-1030.

23. Ferster A, Tahriri P, Vermylen C, et al.Five years of experience with hydrox-yurea, in children and young adultswith sickle cell disease. Blood.2001;97:3628-3632.

24. Wang WC, Helms RW, Lynn HS, et al.Effect of hydroxyurea. on growth inchildren with sickle cell anemia: re-

sults of the H-UG-KIDS Study.JPediatr2002; 140:225-229.

25. Vichinsky EP, Neumayr LD, EarlesAN, et al. Causes and outcomes of theacute chest syndrome in sickle cell dis-ease. National Acute Chest SyndromeStudy Group. N Engl J Med.2000;342:1855-1865.

26. Vichinsky EP, Haberkern CM, Neu-mayr L, et al. A comparison of conserv-ative and aggressive transfusion regi-mens in the perioperative managementof sickle cell disease. The PreoperativeTransfusion in Sickle Cell DiseaseStudy Group. NEnglJ Med. 1995;333:206-213.

27. Vichinsky EP. Current issues withblood transfusions in sickle cell dis-ease. Semin Hematol. 2001;38:14-22.

28. Ohene-Frempong K. Indications forred cell transfusion in sickle cell dis-ease. Semin Hematol. 2001;38:5-13.

29. Ohene-Frempong K. Stroke in sicklecell disease: demographic, clinical,and therapeutic considerations. SeminHematol. 1991;28:213-219.

30. Mantadakis E, Cavender JD, RogersZR, Ewalt DH, Buchanan GR. Preva-lence of priapism in children and ado-lescents with sickle cell anemia.JPedi-atr Hematol Oncol. 1999;21:518-522.

31. Adeyoju AB, Olujohungbe AB, MorrisJ, et al. Priapism in sickle-cell disease;incidence, risk factors and complica-tions-an international multicentrestudy. BJUInt. 2002;90:898-902.

32. Mantadakis E, Ewalt DH, CavenderJD, Rogers ZR, Buchanan GR. Outpa-tient penile aspiration and epineph-rine irrigation for young patients withsickle cell anemia and prolonged pri-apism. Blood. 2000;95:78-82.

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