Review Article
Management of Sickle Cell Disease in Children
Suzie A. Noronha, MD, S. Christy Sadreameli, MD, MHS, and John J. Strouse, MD, PhD
Abstract: Sickle cell disease (SCD) is a heterogeneous inherited disorder
of hemoglobin that causes chronic hemolytic anemia, vaso-occlusion, and
endothelial dysfunction. These physiologic derangements often lead to
multiorgan damage in infancy and throughout childhood. The most com-
mon types of SCD are homozygous hemoglobin S (HbSS disease), he-
moglobin SC disease, and sickle β thalassemia. HbSS disease and
sickle β0 thalassemia often are referred to as sickle cell anemia because
they have similar severity. Screening and preventive measures, including
infection prophylaxis and vaccination, have significantly improved out-
comes for children with SCD. Evidence-based therapies, such as hy-
droxyurea and transfusion, play an important role in preventing
progression of select complications. Many chronic complications develop
insidiously and require multidisciplinary care for effective treatment. Pri-
mary care physicians, as well as physicians in many other disciplines,
may care for these patients and should be familiar with the potential
acute and chronic complications of this disease. This review ad-
dresses healthcare maintenance guidelines, common complications,
and recommendations for management of pediatric patients with SCD.
Key Words: children, healthcare maintenance, primary care, sickle cell
anemia, sickle cell disease
S ickle cell disease (SCD) is an inherited abnormality of hemo-
globin leading to sickling of red blood cells, anemia, and
complications from vaso-occlusion. It is identified in 1 in
300 to 400 African American births and in approximately
From the Department of Pediatrics, University of Rochester, Rochester, New
York, the Department of Pediatrics, Johns Hopkins University School of
Medicine, Baltimore, Maryland, and the Division of Hematology, Duke Uni-
versity School of Medicine, Durham, North Carolina.
Correspondence to Dr John J. Strouse, Division of Hematology, Duke University
School of Medicine, 315 Trent Drive, Ste. 267, Durham, NC 27710. E-mail:
john.strouse@duke.edu. To purchase a single copy of this article, visit sma.
org/smj-home. To purchase larger reprint quantities, please contact
reprints@wolterskluwer.com.
Hydroxyurea has been approved by the US Food and Drug Administration for the
treatment of SCD only in adults. The use of hydroxyurea in children with
SCD is not Food and Drug Administration approved but “recommended,”
and this is an off-label recommendation.
The work described herein was funded by a grant from the Health Services and
Resource Administration (U1EMC27864).
S.A.N. has no financial relationships to disclose and no conflicts of interest to
report. S.C.S. has received compensation from the National Institutes of
Health/National Center for Advancing Translational Sciences. J.J.S. has
received institutional grants from the National Heart, Lung, and Blood
Institute, the Health Resources and Services Administration, the Maryland
Department of Health and Mental Hygiene, Advanced Studies in Medicine,
and serves as an expert witness for the Vaccine Adverse Event Trust Fund.
Accepted July 13, 2016.
Copyright © 2016 by The Southern Medical Association
0038-4348/0–2000/109-495
DOI: 10.14423/SMJ.0000000000000523
Southern Medical Journal • Volume 109, Number 9, September 2016
Copyright © 2016 The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
2000 infants each year in the United States by universal
newborn screening for sickle hemoglobinopathies. From
1991 to 2011, the highest calculated incidence of SCD from
newborn screening data was observed in Washington, DC
(1:437), followed by Mississippi (1:683) and South Carolina
(1:771).1 The majority of infants (60%–65%) are diagnosed as
having homozygous SS disease (HbSS) or are compound het-
erozygotes, co-inheriting hemoglobins S and C (HbSC, 25%–
30%) or hemoglobin S and a β thalassemia mutation (HbSβ0/+
thalassemia, 9%). People with HbSS and HbSβ0 thalassemia,
on average, have more severe disease in contrast to those with
HbSC and HbSβ+ thalassemia.2 Co-inheritance of α-globin mu-
tations or high fetal hemoglobin expression often leads to de-
creased disease severity even in patients with HbSS.3 Median
survival is 40 to 45 years for people with HbSS, 65 years for
people with HbSC, and 73 years for people with HbSβ+.4
SCD causes chronic hemolysis and vascular endothelial
injury, with an increased risk of acute chronic damage to or-
gan systems. Routine screening and education in childhood
are essential to identify complications in the early stages, per-
mitting interventions to minimize long-term morbidity in vul-
nerable patients (Table 1).
Most infants identified as having SCD on newborn screen-
ing are referred to their local hemoglobinopathy center for ongo-
ing surveillance. The first visit to the pediatric hematologist can
be difficult for families, particularly when no previous family
members have had SCD. The high level of fetal hemoglobin of
infancy is generally protective, yet infants with SCD may expe-
rience a number of complications. A discussion of the full spec-
trum of complications usually is reserved for later visits, after the
family has processed and assimilated the diagnosis. The first
visit includes education about common complications in in-
fancy, such as fever, dactylitis, and splenic sequestration.
Key Points
• Regular healthcare maintenance and ongoing education of the
family and patient are critical for the prevention of long-term
morbidity in pediatric patients with sickle cell disease (SCD).
• Evidence-based interventions such as hydroxyurea and transfu-
sions can prevent some of the significant complications of SCD.
• Physicians in many different disciplines may care for these
children; therefore, awareness of the complications of SCD
and partnership with pediatric hematologists will help ensure
good outcomes.
495
Noronha et al • Management of SCD in Children
Acute and Chronic Complications by
Organ System
Cardiopulmonary Disease
Acute chest syndrome (ACS) is the second most common
reason for hospitalization4 and the leading cause of death in pa-
tients with SCD.5,6 Defined as a new infiltrate on chest radiogra-
phy and one or more signs or symptoms of lower respiratory
tract disease (eg, fever, cough, chest pain, hypoxemia, dyspnea,
tachypnea), ACS is caused by in situ sickling, infection, or em-
boli from infarcted bone marrow. Children with asthma or lower
airway obstruction have a higher risk of developing ACS.7,8
ACS can be mild to severe, including progression to respiratory
and multiorgan system failure. Initial management of ACS in-
cludes oxygen support, appropriate pain control, a parenteral
cephalosporin and oral macrolide, and incentive spirometry. If
the patient’s clinical status declines, then simple transfusion to
a hemoglobin of 10 g/dL or red cell exchange transfusion for se-
vere ACS is warranted to improve oxygen-carrying capacity and
alleviate ventilation-perfusion mismatch.
Respiratory symptoms (wheezing), lower airway obstruc-
tion, and the diagnosis of asthma (20%–48%) are common in
children with SCD and are associated with more frequent pain,
ACS, and increased mortality.8–10 Other pulmonary function ab-
normalities include restrictive lung disease, which becomes
more common with increasing age, and mixed obstruction/
restriction. Sleep-disordered breathing was frequent in the Sleep
and Asthma Cohort study: 41% of children with SCD had mild
obstructive sleep apnea (OSA; apnea-hypopnea index ≥1) and
10% had moderate to severe OSA (apnea-hypopnea index
≥5).11 Hypoxemia, hypercapnia, and acidosis may occur as
a result of OSA and may increase sickling of red blood cells.
Despite the established risks associated with asthma and pul-
monary function abnormalities in SCD, data related to early
intervention/treatment and the role of screening and preven-
tion are lacking. The 2014 National Heart, Lung, and Blood
Institute (NHLBI) guidelines do not recommend routine screen-
ing of asymptomatic patients with SCD with pulmonary func-
tion tests or sleep studies.12 The guidelines do recommend
screening for signs and symptoms during clinical encounters.
Children with asthma symptoms or wheezing should be treated
according to asthma guidelines, with a low threshold for referral
to an asthma specialist. Pulmonary function tests should be con-
sidered in children with recurrent ACS episodes or with severe
or uncontrolled asthma.13 Children with SCD who snore should
undergo a diagnostic nocturnal polysomnogram.
Pulmonary hypertension (elevated resting mean arterial
pressure of ≥25 mm Hg) occurs in SCD because of chronic vas-
cular changes that result from arginine depletion, impaired nitric
oxide bioavailability, and the release of free hemoglobin from
red blood cells. It also can develop secondary to chronic pul-
monary or thromboembolic disease in SCD. Both pulmonary
arterial and venous hypertension occur in SCD. Screening
496
Copyright © 2016 The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
echocardiography showing elevated tricuspid regurgitant ve-
locity (≥250 cm/second) is associated with increased morbid-
ity and mortality in adults with SCD.14 This correlates poorly
with pulmonary artery pressures by catheterization, and there
is no increased mortality in children with SCD and increased
tricuspid regurgitant velocity.15 The 2014 NHLBI guidelines
do not recommend for or against routine screening of asymp-
tomatic children or adults with SCD with echocardiograms be-
cause the evidence is insufficient12; however; an echocardiogram
should be considered to evaluate unexplained hypoxemia; exer-
cise intolerance; and advanced lung disease, including restric-
tive lung disease.
Gastrointestinal System
Chronic hemolysis can cause cholelithiasis with pigment
stones in 10% to 50% in children with SCD.16–19 Children
may be initially asymptomatic or may present with right upper
quadrant pain and jaundice, which are associated with direct
hyperbilirubinemia. Cholecystectomy is recommended in pa-
tients with symptoms to prevent complications such as choledo-
cholithiasis, cholecystitis, ascending cholangitis, or pancreatitis.
Children, particularly with sickle cell anemia (SCA), can
develop sickle hepatopathy or intrahepatic cholestasis, with di-
rect hyperbilirubinemia, as high as 13 to 76 mg/dL, without ev-
idence of infection or bile duct obstruction. Some patients have
mild disease without hepatic dysfunction, whereas others de-
velop fulminant liver failure. Emergent exchange transfusion ap-
pears to be the only effective therapy for severe cases.20,21
Genitourinary System
Boys with SCD and their parents should be educated about
priapism, which can affect males of all ages with any sickle ge-
notype. Priapism may occur in a stuttering (multiple episodes
lasting <2–3 hours) or prolonged manner. Home interventions
include exercise, warm baths, ejaculation, urination, analgesics,
and increased hydration. Patients are instructed to seek medical
attention if priapism lasts for >4 hours to prevent fibrosis and
impotence. In the emergency department setting, intravenous
fluids, pain control, and aspiration and irrigation of the corpus
cavernosum and intrapenile injection of α-adrenergic agents of-
ten are used. Erectile dysfunction ultimately develops in approx-
imately 40% of men who experience recurrent episodes of
priapism.22 We recommend against transfusion for the immedi-
ate therapy of priapism.15
Immune System/Spleen
The onset of splenic dysfunction occurs as early as
5 months of age23 and results in greatly increased infections with
encapsulated organisms such as Streptococcus pneumoniae and
Haemophilus influenzae type B. Before routine prophylaxis
with penicillin, the incidence of bacteremia ranged from 3.7
to 8.3 cases per 100 person-years, and pneumococcal and
Haemophilus infections were associated with 14.5% and 20%
© 2016 The Southern Medical Association

mortality rates.2 In a randomized, double-blinded, placebo-
controlled trial, Gaston et al reported an 84% reduction in pneu-
mococcal sepsis in the penicillin group.24 Penicillin 125 mg
twice daily is strongly recommended for all infants with SCA,
increasing to 250 mg twice daily at age 3, and continuing until
the child is at least 5 years old. Morbidity and mortality from in-
fection have declined substantially as a result of antibiotic pro-
phylaxis and inclusion of conjugated pneumococcal and
Haemophilus influenzae type B vaccines in infancy. The benefit
for children with HbSC and HbSβ+ is unclear, but many pediat-
ric hematologists still recommend prophylactic measures.
Although pneumococcal sepsis is a rare event, infection in
fully immunized patients still occurs.25,26 Fever also may signify
other infections such as parvovirus, pyelonephritis, cholecystitis,
osteomyelitis, or ACS. Providers should reinforce the impor-
tance of preventing infections by penicillin prophylaxis and im-
munizations and being evaluated immediately for fevers of
101.3°F (38.5°C) or higher. A complete blood count (CBC) with
differential and reticulocyte counts should be compared with
baseline values. Peripheral blood cultures should be obtained
before the administration of parenteral antibiotics, usually a
third-generation cephalosporin. Additional studies such as
chest radiography or urine culture may be indicated, depending
on clinical features.
Aplastic crisis may accompany a febrile illness. Parvovirus
B19 is the most common cause of aplastic crisis in patients with
SCD, although other viral infections can cause myelosup-
pression. Parvovirus infects erythrocyte precursors, suppresses
erythropoiesis, and causes severe anemia in people with high
red cell turnover. Children with aplastic crisis may present with
syncope or hypotension or with gradual worsening of fatigue
and pallor. The anemia often is severe and the reticulocyte count
is typically <1%. Patients with symptomatic or severe anemia
caused by aplastic crisis should receive slow, small-aliquot
transfusions to avoid congestive heart failure. Patients with
high baseline reticulocyte counts who do not require immedi-
ate transfusion should be studied closely with a daily CBC
and reticulocyte count until no longer reticulocytopenic to en-
sure transfusion, if needed.
Splenic sequestration is another common cause of acute ex-
acerbation of anemia.2 Most children with HbSS autoinfarct their
spleen by age 4 years, whereas patients with HbSC and HbSβ
thalassemia typically retain significant splenic tissue longer.27 Be-
fore autoinfarction, children may experience rapid enlargement
of the spleen caused by sequestration of sickled cells. The spleen
examination is taught to the family during their initial visits be-
cause they are often the first to detect splenomegaly. Children
with severe sequestration are at risk for shock and usually
have a decrease in hemoglobin of ≥2 g/dL from baseline,
reticulocytosis, and thrombocytopenia. Support of intravascular
volume and restoration of oxygen-carrying capacity are war-
ranted; small transfusions of packed red blood cells (5 mL/kg)
should be considered because often the spleen subsequently
releases sequestered erythrocytes. Recurrence is common;
Southern Medical Journal • Volume 109, Number 9, September 2016
Copyright © 2016 The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
Review Article
therefore, splenectomy is recommended in patients with recurrent
acute splenic sequestration or symptomatic hypersplenism.28–30
Neurologic System
Acute painful vaso-occlusive crisis (VOC) is the most com-
mon symptom and reason for hospitalization among children
with SCD. Although vaso-occlusion is the hallmark event lead-
ing to pain, complex interactions between cellular and molecular
mediators may initiate and propagate the event. Further elucida-
tion of these factors may lead to the development of innovative
targeted therapies.31,32 VOC in young children often affects the
hands and feet, causing swelling and tenderness, which is called
dactylitis. Mild to moderate pain can be managed at home with
heat, distraction, ibuprofen, and oral opiates. Severe pain should
be treated within 30 minutes of triage or 60 minutes of registra-
tion for emergency care with maintenance fluids if the child is
unable to drink, anti-inflammatory agents, and opiates. Severe
pain necessitates treatment with parenteral opiates, which can
be administered on a scheduled basis or by patient-controlled an-
algesia. Investigation of causes of pain other than SCD can occur
simultaneously with pain management. An individualized proto-
col, developed by the patient and his or her SCD medical team,
can be helpful to expedite the patient’s care in the acute setting.
Patients can be discharged from the hospital once their pain can
be managed with oral analgesics. We recommend encouraging
ambulation and incentive spirometry to reduce the risk of ACS.
Oxygen should be reserved for patients with arterial oxygen satu-
ration <95% and transfusion avoided in those with acute pain and
no other indication for transfusion.11
Chronic pain is a challenging complication in adolescents
and adults with SCD, affecting quality of life and productivity.
Pain is defined as chronic if it lasts more than 3 months. It can
result from chronic injury to joints, as in avascular necrosis,
which leads to characteristic radiographic changes in later
stages; patients may benefit from physical therapy or surgical in-
terventions if the pain is severe. Chronic inflammation and re-
perfusion injury to tissues and nerves can lead to peripheral
nerve damage and central sensitization, manifesting as allodynia
and hyperalgesia.31 Chronic pain can be deep and achy in nature
or can be neuropathic, with patients complaining of burning,
numbness, or tingling. Symptoms of pain may be compounded
by concurrent mood disorder, social isolation, poor self-esteem,
shame, and other factors. Treatment is difficult and may involve
a combination of nonsteroidal anti-inflammatory agents; judicious
opioid use; anticonvulsants; antidepressants; and multidisciplinary
approaches, including massage, acupuncture, physical therapy,
or cognitive-behavioral therapy.
The Centers for Disease Control and Prevention has issued
guidelines on the use of chronic opioids, given the alarming na-
tionwide increase in opioid-related morbidity and deaths; how-
ever, these guidelines do not apply to children, nor do they
specifically address the nuances of pain management associated
with SCD.33 There is a paucity of data on appropriate opioid
497
Noronha et al • Management of SCD in Children
practices, development of tolerance or addiction, and nonopioid
pharmacologic options for SCD-associated acute and chronic
pain. We recommend using functional outcomes to evaluate
the effectiveness of opiates and other strategies to treat pain in
people with SCD. It is important to minimize the potential harms
of opiates by obtaining appropriate informed consent (opiate
agreement) and monitoring for opiate misuse, diversion, addic-
tion, and symptoms of withdrawal in patients treated frequently
with opiates. Tolerance is common in those treated with daily
opiates for >1 week and should be expected with appropriate in-
creases in opiate doses if needed.
Hemorrhagic or ischemic stroke historically has occurred in
11% of individuals with SCA before age 20 years.34 Patients
typically present with facial droop, hemiparesis, seizure, dysar-
thria, headache, and/or aphasia.35 Magnetic resonance imaging
(MRI) is preferred to demonstrate the changes associated with
acute infarction, and MR angiography most often reveals ob-
struction or stenosis of the internal carotid artery, middle,
and/or anterior cerebral artery. Prompt exchange transfusion
is the preferred intervention for these patients. Significant and
rapid reduction in the hemoglobin S fraction may be more effec-
tive in preventing recurrence than simple transfusion to a hemo-
globin concentration >10 g/dL while the hemoglobin S is >30%
as this increases the viscosity of whole blood.36–38 After the pa-
tient has been stabilized, chronic transfusions to maintain hemo-
globin S ≤30% are instituted as secondary prophylaxis.
Approximately 40% of children with ischemic stroke will have
moyamoya syndrome, obstruction of the large cerebral arteries
with collateral blood vessels that give the appearance of a puff
of smoke on conventional angiography.39 These children are at
a much higher risk of recurrent stroke, and some pediatric hema-
tologists and neurosurgeons recommend revascularization pro-
cedures or bone marrow transplantation to decrease this
risk.40–42
Transcranial Doppler is an effective screening tool to iden-
tify children at increased risk of stroke and is recommended an-
nually for patients ages 2 to 16 years with SCA.10,43 Children
with elevated cerebral blood flow velocity (>200 cm/second)
were randomly assigned to chronic transfusions to decrease
hemoglobin S to ≤30% or observation. Chronic transfu-
sions reduced the risk of stroke from 30% to 3% during a
30-month period.44
Central nervous system disease continues to be a problem
despite the decreased incidence of large-vessel cerebral infarc-
tion with transcranial Doppler screening. Cerebral ischemia de-
tected on MRI without associated neurologic deficit is referred
to as silent cerebral infarct (SCI) and is most prevalent in chil-
dren with SCA, but it also is seen in patients with HbSC and
HbSβ+. Risk factors for the development of SCI include epi-
sodes of acute anemia, chronic anemia <7 g/dL, higher systolic
blood pressure, male sex, and internal carotid stenosis.45–47
SCI has been detected in young children with HbSS, with a re-
ported prevalence ranging from 11% (15 months of age) to
27.7% by 3.4 years48,49 and from 5% to 13.5% in children
498
Copyright © 2016 The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
with HbSC.50,51 Prevalence increases with age into adulthood,
suggesting ongoing injury. SCI is associated with worse neuro-
cognitive outcomes and increased risk of overt stroke.52,53 In a
controlled multicenter trial, chronic transfusions in patients with
SCI were shown to decrease the incidence of new SCI and overt
stroke, but no difference in IQ was seen during this 3-year
trial.54 Based on the results of this study, some SCD experts rec-
ommend screening children with SCA at age 5 years for SCI by
MRI and for all patients with poor academic performance. Cog-
nitive impairment also is more prevalent in children with SCA
and normal brain MRIs compared with their siblings without
SCD, and it is associated with more severe anemia, low pulse
oximetry, older age, and socioeconomic factors such as head
of household education and family income.55,56
Ophthalmologic Disease
Proliferative retinopathy occurs in children and more often
affects patients with HbSC. Annual incidence rates were 0.5
cases (95% confidence interval 0.3– 0.8) per 100 subjects with
HbSS and 2.5 cases (95% confidence interval 1.9–3.3) per
100 patients with HbSC in the Jamaican Cohort Study.57 The
prevalence has been reported to be 45% of patients with HbSC,
11% of patients with HbSS, and 17% of patients with sickle β
thalassemia by early adulthood.58 Retinal ischemia and neovas-
cularization eventually develop, leading to retinal detachment
and loss of visual acuity. Annual dilated ophthalmologic exam-
ination is recommended for patients beginning at age 10 years
to detect early retinal injury. Ophthalmologic interventions for
proliferative retinopathy include laser photocoagulation and vit-
rectomy in severe cases of vitreous hemorrhage.
Renal Disease
Sickle vasculopathy impairs both renal tubular and glomer-
ular function. Children with SCD commonly have frequent uri-
nation and nocturnal enuresis because of their inability to
concentrate their urine (hyposthenuria). Maintenance of good
hydration is a critical piece of advice for these patients. Screen-
ing for microalbuminuria starting at age 10 years may identify
patients at increased risk for chronic kidney disease.59 Children
with microalbuminuria or modest elevations in serum creati-
nine (>0.7 mg/dL) should be referred to a pediatric nephrolo-
gist. Renal dysfunction progresses with age manifesting as
microalbuminuria, proteinuria, glomerular sclerosis, and, in
some patients, chronic renal failure. Proteinuria has been re-
ported in 6.2% to 41%, and chronic kidney disease has been
reported in 8% to 26.5% of children; the rate of both condi-
tions increases with age.59–61 End-stage renal disease occurs
in approximately 2% to 4% of adults with SCD62,63 and was
identified as an independent predictor of early mortality.4,64
Angiotensin-converting enzyme inhibitors are prescribed com-
monly for their renoprotective effects; Falk et al reported a de-
cline in proteinuria after short-term use of enalapril in a small
number of adults with SCD.54 Hydroxyurea (HU) may partially
© 2016 The Southern Medical Association

Table 1. Healthcare maintenance in SCD
Complication Preventive measure
Pneumococcal sepsis Penicillin 125 mg when <3 y old,
250 mg when ≥3 y old
Prevnar-13 series
Pneumovax-23
Meningococcal Hib-MenCY-TT or equivalent
disease Meningococcal polysaccharide
Stroke Transcranial Doppler HbSS, HbSβ0 thalassemia
Retinopathy Dilated retinal examination
Nephropathy Urinalysis with microscopy
Hib-MenCY-TT, Haemophilus b tetanus toxoid conjugate vaccine; SCD, sickle cell disease.
preserve concentrating ability and decrease glomerular hyper-
trophy and hyperfiltration.65,66
Treatment with HU
HU is the only US Food and Drug Administration–approved
disease-modifying therapy for SCD. It is a ribonucleotide reduc-
tase antagonist that increases fetal hemoglobin production and
total hemoglobin. HU also reduces the neutrophil count and in-
tracellular adhesion and increases nitric oxide bioavailability,
which may account for some of the clinical benefits.67–70 Multi-
ple clinical trials in children and adults have demonstrated the
benefits of HU on rates of VOC, ACS, quality of life, hospitali-
zation, and mortality.71–76 There is no diminution of growth or
pubertal development, even after chronic use.77,78 The pediatric
hydroxyurea phase III clinical trial, more commonly known as
BABY HUG, established a favorable safety and efficacy profile
for HU in children as young as 9 months old.79 The main ad-
verse effects of HU for both children and adults include neutro-
penia, thrombocytopenia, rash, and nail changes.
Based on the NHLBI guidelines published in 2014, chil-
dren 9 months and older with SCA should be offered HU at a
starting dose of 20 mg/kg/day. CBC with differential and reticu-
locyte count should be monitored every 4 weeks for cytopenias,
with a goal absolute neutrophil count of between 2000 and
4000/μL and a platelet count ≥80,000/μL. The dose may be es-
calated by 5 mg/kg every 8 weeks to the maximum tolerated
dose of 35 mg/kg/day based on clinical or laboratory findings.
Once the patient is taking a stable dose, laboratory values may
be monitored every 2 to 3 months.10 HU can be considered on
a case-by-case basis for patients with HbSC or HbSβ+ and mod-
erate to severe symptoms. It is possible that HU could replace
chronic transfusions in some patients receiving them for an ele-
vated cerebral blood flow velocity.80
Treatment with Transfusion
Transfusion of sickle-negative red blood cells is an effec-
tive treatment for several acute and chronic complications of
SCD and includes simple and exchange analysis transfusions.
Southern Medical Journal • Volume 109, Number 9, September 2016
Copyright © 2016 The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
Review Article
Genotype Age to start Frequency
All Upon diagnosis Twice daily until ≥5 y old
All 2 mo Per infant vaccine schedule
All 2y Once at 2 y old, second booster 3–5 y later
All 2 mo 2, 4, 6, and 12–15 mo
2y 2 boosters separated by 8–12 wk, then
every 5 y thereafter
2y Annually
All 10 y Annually
All 10 y Annually
Simple transfusions are indicated in patients with low hemo-
globin concentration, because transfusion above a hemoglo-
bin concentration of 10 g/dL with hemoglobin S >30% can
cause hyperviscosity and increased vaso-occlusive complica-
tions, as well as the following complications: splenic sequestra-
tion with severe anemia, moderate ACS, and symptomatic
anemia. Either simple or exchange transfusion is effective for
hepatic or intrahepatic sequestration, multiorgan failure syn-
drome, or acute stroke, but exchange transfusion is preferred
for these complications if readily available and for severe
ACS. Patients receiving chronic transfusion for primary or sec-
ondary stroke prophylaxis can be treated with either simple or
exchange transfusions. Transfusion, however, is neither neces-
sary nor effective for the treatment of asymptomatic anemia,
chronic splenic sequestration, or acute vaso-occlusive pain
in children with SCD (Table 2). The major risks of transfusion
in people with SCD are iron overload and alloimmunization to
minor blood group antigens. Iron overload occurs in all patients
receiving chronic simple transfusions but only a small proportion
of those receiving exchange transfusions.81 Alloimmunization to
minor antigens on red blood cells occurs in 12% of children and
up to 27% of adults and can cause delayed hemolytic transfu-
sion reactions and delays in transfusion secondary to diffi-
culty obtaining compatible units.82,83 We recommend following a
standardized protocol for chronically transfused children with
SCD, including monitoring and treating iron overload and phe-
notypically matched blood for the C, E, and K antigens.
Conclusions
SCD can cause frequent severe pain and life-threatening compli-
cations involving multiple organ systems in children. These
complications can be minimized through education and partner-
ship between primary care providers and pediatric hematologists
to provide SCD-specific healthcare maintenance. In addition,
specific treatments including HU and regular transfusions can
prevent many of the complications of SCD, and analgesics, anti-
biotics, and blood transfusion are needed frequently as treat-
ments for acute complications. Useful resources for providers
499
Noronha et al • Management of SCD in Children

Table 2. Indications for transfusion from NHLBI Evidence-Based Management of Sickle Cell Disease, Expert Panel
Report, 2014

Complication Transfusion Strength of recommendation Evidence

Anemia, asymptomatic No Consensus-expert panel
Kidney injury (unless multisystem organ failure) No Consensus-expert panel
Pain crisis, uncomplicated No Moderate Low
Priapism No Moderate Low
Splenic sequestration, chronic No Low Low
Splenic sequestration, severe anemia Simple Strong Low
ACS, severe Exchange Strong Low
ACS, moderate Simple Moderate Low
Anemia, symptomatic Simple Consensus-expert panel
Aplastic crisis Simple Consensus-expert panel
Hepatic sequestration Eithera Consensus-expert panel
Intrahepatic sequestration Either Consensus-expert panel
Multisystem organ failure Either Consensus-expert panel
Stroke, acute Either Moderate Low
Before surgery with general anesthesia Consult Moderate to strong Low
Increased stroke risk (TCD reading >200 cm/s) Chronicb Strong High
Prior stroke Chronic Moderate Low

ACS, acute chest syndrome; NHLBI, National Heart, Lung, and Blood Institute; TCD, transcranial Doppler.
a
Either indicates either simple or exchange transfusion.
b
Chronic, transfusions typically every 4 weeks to maintain a trough HbS <30%.

of care to people with SCD include the National Heart, Lung,
and Blood Institute’s Evidence-Based Management of Sickle
Cell Disease: Expert Panel Report, 2014 and the American So-
ciety of Hematology’s sickle cell pocket guides and smartphone
app based on this report.12,84–86
References
1. Therrell BL Jr, Lloyd-Puryear MA, Eckman JR, et al. Newborn screening for
sickle cell diseases in the United States: a review of data spanning 2 decades.
Semin Perinatol 2015;39:238–251.
2. Gill FM, Sleeper LA, Weiner SJ, et al. Clinical events in the first decade in a
cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell
Disease Blood 1995;86:776–783.
3. Sheehan VA, Luo Z, Flanagan JM, et al. Genetic modifiers of sickle cell
anemia in the BABY HUG cohort: influence on laboratory and clinical
phenotypes. Am J Hematol 2013;88:571–576.
4. 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–
1644.
5. Brousseau DC, Owens PL, Mosso AL, et al. Acute care utilization and
rehospitalizations for sickle cell disease. JAMA 2010;303:1288–1294.
6. Quinn CT, Rogers ZR, McCavit TL, et al. Improved survival of children and
adolescents with sickle cell disease. Blood 2010;115:3447–3452.
7. Boyd JH, DeBaun MR, Morgan WJ, et al. Lower airway obstruction is
associated with increased morbidity in children with sickle cell disease.
Pediatr Pulmonol 2009;44:290–296.
8. Boyd JH, Macklin EA, Strunk RC, et al. Asthma is associated with acute
chest syndromze and pain in children with sickle cell anemia. Blood
2006;108:2923–2927.
9. Boyd JH, Macklin EA, Strunk RC, et al. Asthma is associated with
increased mortality in individuals with sickle cell anemia. Haematologica
2007;92:1115–1118.
10. Strunk RC, Cohen RT, Cooper BP, et al. Wheezing symptoms and parental
asthma are associated with a physician diagnosis of asthma in children
with sickle cell anemia. J Pediatr 2014;164:821.e1–826.e1.
11. Rosen CL, Debaun MR, Strunk RC, et al. Obstructive sleep apnea and sickle
cell anemia. Pediatrics 2014;134:273–281.
12. US Department of Health and Human Services. Evidence-based
management of sickle cell disease: expert panel report 2014. https://www.
nhlbi.nih.gov/sites/www.nhlbi.nih.gov/files/sickle-cell-disease-report.pdf.
Accessed July 14, 2016.
13. Anim SO, Strunk RC, DeBaun MR. Asthma morbidity and treatment in
children with sickle cell disease. Expert Rev Respir Med 2011;5:635–645.
14. Gladwin MT, Sachdev V, Jison ML, et al. Pulmonary hypertension as
a risk factor for death in patients with sickle cell disease. NEJM
2004;350:886–895.
15. Hebson C, New T, Record E, et al. Elevated tricuspid regurgitant velocity as a
marker for pulmonary hypertension in children with sickle cell disease: less
prevalent and predictive than previously thought? J Pediatr Hematol Oncol
2015;37:134–139.
16. Karayalcin G, Hassani N, Abrams M, et al. Cholelithiasis in children with
sickle cell disease. Am J Dis Child 1979;133:306–307.
17. Lachman BS, Lazerson J, Starshak RJ, et al. The prevalence of cholelithiasis
in sickle cell disease as diagnosed by ultrasound and cholecystography.
Pediatrics 1979;64:601–603.
18. Mintz AA, Church G, Adams ED. Cholelithiasis in sickle cell anemia.
J Pediatr 1955;47:171–177.
19. Walker TM, Hambleton IR, Serjeant GR. Gallstones in sickle cell
disease: observations from the Jamaican Cohort study. J Pediatr
2000;136:80–85.
20. Ahn H, Li CS, Wang W. Sickle cell hepatopathy: clinical presentation,
treatment, and outcome in pediatric and adult patients. Pediatr Blood
Cancer 2005;45:184–190.
21. Buchanan GR, Glader BE. Benign course of extreme hyperbilirubinemia in
sickle cell anemia: analysis of six cases. J Pediatr 1977;91:21–24.

500 © 2016 The Southern Medical Association

Copyright © 2016 The Southern Medical Association. Unauthorized reproduction of this article is prohibited.

22. Anele UA, Burnett AL. Erectile dysfunction after sickle cell disease-
associated recurrent ischemic priapism: profile and risk factors. J Sex Med
2015;12:713–719.
23. Pearson HA, McIntosh S, Ritchey AK, et al. Developmental aspects of
splenic function in sickle cell diseases. Blood 1979;53:358–365.
24. Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in
children with sickle cell anemia. A randomized trial. N Engl J Med
1986;314:1593–1599.
25. Ellison AM, Ota KV, McGowan KL, et al. Pneumococcal bacteremia in a
vaccinated pediatric sickle cell disease population. Pediatr Infect Dis J
2012;31:534–536.
26. Santoro JD, Case AE, El-Dahr J, et al. A case of invasive Streptococcus
pneumoniae in an afebrile adolescent with sickle cell disease. Clin Pediatr
(Phila) 2013;52:1173–1175.
27. Brown AK, Sleeper LA, Miller ST, et al. Reference values and hematologic
changes from birth to 5 years in patients with sickle cell disease.
Cooperative Study of Sickle Cell Disease. Arch Pediatr Adolesc Med
1994;148:796–804.
28. Topley JM, Rogers DW, Stevens MC, et al. Acute splenic sequestration and
hypersplenism in the first five years in homozygous sickle cell disease. Arch
Dis Child 1981;56:765–769.
29. Kinney TR, Ware RE, Schultz WH, et al. Long-term management of
splenic sequestration in children with sickle cell disease. J Pediatr
1990;117:194–199.
30. Powell RW, Levine GL, Yang YM, et al. Acute splenic sequestration crisis in
sickle cell disease: early detection and treatment. J Pediatr Surg
1992;27:215–218.
31. Ballas SK, Gupta K, Adams-Graves P. Sickle cell pain: a critical reappraisal.
Blood 2012;120:3647–3656.
32. Manwani D, Frenette PS. Vaso-occlusion in sickle cell disease: path-
ophysiology and novel targeted therapies. Blood 2013;122:3892–3898.
33. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing
opioids for chronic pain—United States, 2016. MMWR Recomm Rep
2016;65:1–49.
34. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents
in sickle cell disease: rates and risk factors. Blood 1998;91:288–294.
35. Strouse JJ, Hulbert ML, DeBaun MR, et al. Primary hemorrhagic stroke in
children with sickle cell disease is associated with recent transfusion and
use of corticosteroids. Pediatrics 2006;118:1916–1924.
36. 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;149:710–712.
37. Hurlet-Jensen AM, Prohovnik I, Pavlakis SG, et al. Effects of total
hemoglobin and hemoglobin S concentration on cerebral blood flow
during transfusion therapy to prevent stroke in sickle cell disease. Stroke
1994;25:1688–1692.
38. Kassim AA, Galadanci NA, Pruthi S, et al. How I treat and manage strokes in
sickle cell disease. Blood 2015;125:3401–3410.
39. Dobson SR, Holden KR, Nietert PJ, et al. Moyamoya syndrome in childhood
sickle cell disease: a predictive factor for recurrent cerebrovascular events.
Blood 2002;99:3144–3150.
40. Fasano RM, Meier ER, Hulbert ML. Cerebral vasculopathy in children with
sickle cell anemia. Blood Cells Mol Dis 2015;54:17–25.
41. Griessenauer CJ, Lebensburger JD, Chua MH, et al. Encephal-
oduroarteriosynangiosis and encephalomyoarteriosynangiosis for treat-
ment of moyamoya syndrome in pediatric patients with sickle cell
disease. J Neurosurg Pediatr 2015;16:64–73.
42. Hankinson TC, Bohman LE, Heyer G, et al. Surgical treatment of moyamoya
syndrome in patients with sickle cell anemia: outcome following
encephaloduroarteriosynangiosis. J Neurosurg Pediatr 2008;1:211–216.
43. Adams RJ, McKie VC, Carl EM, et al. Long-term stroke risk in children
with sickle cell disease screened with transcranial Doppler. Ann Neurol
1997;42:699–704.
Southern Medical Journal • Volume 109, Number 9, September 2016
Copyright © 2016 The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
Review Article
44. 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.
45. Bernaudin F, Verlhac S, Arnaud C, et al. Chronic and acute anemia and
extracranial internal carotid stenosis are risk factors for silent cerebral
infarcts in sickle cell anemia. Blood 2015;125:1653–1661.
46. Dowling MM, Quinn CT, Plumb P, et al. Acute silent cerebral ischemia and
infarction during acute anemia in children with and without sickle cell
disease. Blood 2012;120:3891–3897.
47. DeBaun MR, Sarnaik SA, Rodeghier MJ, et al. Associated risk factors
for silent cerebral infarcts in sickle cell anemia: low baseline hemo-
globin, sex, and relative high systolic blood pressure. Blood 2012;
119:3684–3690.
48. Wang WC, Langston JW, Steen RG, et al. Abnormalities of the central
nervous system in very young children with sickle cell anemia. J Pediatr
1998;132:994–998.
49. Kwiatkowski JL, Zimmerman RA, Pollock AN, et al. Silent infarcts in young
children with sickle cell disease. Br J Haematol 2009;146:300–305.
50. Guilliams KP, Fields ME, Hulbert ML. Higher-than-expected prevalence
of silent cerebral infarcts in children with hemoglobin SC disease. Blood
2015;125:416–417.
51. Pegelow CH, Macklin EA, Moser FG, et al. Longitudinal changes in brain
magnetic resonance imaging findings in children with sickle cell disease.
Blood 2002;99:3014–3018.
52. Armstrong FD, Thompson RJ Jr, Wang W, 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;97:864–870.
53. Bernaudin F, Verlhac S, Freard F, et al. Multicenter prospective study of
children with sickle cell disease: radiographic and psychometric correlation.
J Child Neurol 2000;15:333–343.
54. DeBaun MR, Gordon M, McKinstry RC, et al. Controlled trial of
transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med
2014;371:699–710.
55. Kawadler JM, Clayden JD, Clark CA, et al. Intelligence quotient in paediatric
sickle cell disease: a systematic review and meta-analysis. Dev Med Child
Neurol 2016;58:672–679.
56. King AA, Strouse JJ, Rodeghier MJ, et al. Parent education and biologic
factors influence on cognition in sickle cell anemia. Am J Hematol
2014;89:162–167.
57. Downes SM, Hambleton IR, Chuang EL, et al. Incidence and natural history
of proliferative sickle cell retinopathy: observations from a cohort study.
Ophthalmology 2005;112:1869–1875.
58. Clarkson JG. The ocular manifestations of sickle-cell disease: a prevalence
and natural history study. Trans Am Ophthalmol Soc 1992;90:481–504.
59. Yee MM, Jabbar SF, Osunkwo I, et al. Chronic kidney disease and albuminuria
in children with sickle cell disease. Clin J Am Soc Nephrol 2011;6:2628–2633.
60. Marsenic O, Couloures KG, Wiley JM. Proteinuria in children with sickle
cell disease. Nephrol Dial Transplant 2008;23:715–720.
61. Wigfall DR, Ware RE, Burchinal MR, et al. Prevalence and clinical
correlates of glomerulopathy in children with sickle cell disease. J Pediatr
2000;136:749–753.
62. Falk RJ, Scheinman J, Phillips G, et al. Prevalence and pathologic features of
sickle cell nephropathy and response to inhibition of angiotensin-converting
enzyme. N Engl J Med 1992;326:910–915.
63. Powars DR, Elliott-Mills DD, Chan L, et al. Chronic renal failure in sickle
cell disease: risk factors, clinical course, and mortality. Ann Intern Med
1991;115:614–620.
64. Powars DR, Chan LS, Hiti A, et al. Outcome of sickle cell anemia: a
4-decade observational study of 1056 patients. Medicine (Baltimore)
2005;84:363–376.
65. Alvarez O, Miller ST, Wang WC, et al. Effect of hydroxyurea treatment on
renal function parameters: results from the multi-center placebo-controlled
BABY HUG clinical trial for infants with sickle cell anemia. Pediatr Blood
Cancer 2012;59:668–674.
501
Noronha et al • Management of SCD in Children
66. Aygun B, Mortier NA, Smeltzer MP, et al. Hydroxyurea treatment decreases
glomerular hyperfiltration in children with sickle cell anemia. Am J Hematol
2013;88:116–119.
67. Almeida CB, Souza LE, Leonardo FC, et al. Acute hemolytic vascular
inflammatory processes are prevented by nitric oxide replacement or a
single dose of hydroxyurea. Blood 2015;126:711–720.
68. Bartolucci P, Chaar V, Picot J, et al. Decreased sickle red blood cell adhesion
to laminin by hydroxyurea is associated with inhibition of Lu/BCAM protein
phosphorylation. Blood 2010;116:2152–2159.
69. Chaar V, Laurance S, Lapoumeroulie C, et al. Hydroxycarbamide decreases
sickle reticulocyte adhesion to resting endothelium by inhibiting endothelial
lutheran/basal cell adhesion molecule (Lu/BCAM) through phosphodiesterase
4A activation. J Biol Chem 2014;289:11512–11521.
70. Lou TF, Singh M, Mackie A, et al. Hydroxyurea generates nitric oxide in
human erythroid cells: mechanisms for gamma-globin gene activation. Exp
Biol Med (Maywood) 2009;234:1374–1382.
71. Ballas SK, Barton FB, Waclawiw MA, et al. Hydroxyurea and sickle
cell anemia: effect on quality of life. Health Qual Life Outcomes
2006;4:59.
72. Charache S, Barton FB, Moore RD, et al. Hydroxyurea and sickle cell
anemia. Clinical utility of a myelosuppressive "switching" agent. The
Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Medicine
(Baltimore) 1996;75:300–326.
73. 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;289:1645–1651.
74. 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;115:2354–2363.
75. Strouse JJ, Lanzkron S, Beach MC, et al. Hydroxyurea for sickle cell
disease: a systematic review for efficacy and toxicity in children.
Pediatrics 2008;122:1332–1342.
502
Copyright © 2016 The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
76. Thornburg CD, Files BA, Luo Z, et al. Impact of hydroxyurea on clinical
events in the BABY HUG trial. Blood 2012;120:4304–4310.
77. Hankins JS, Aygun B, Nottage K, et al. From infancy to adolescence: fifteen
years of continuous treatment with hydroxyurea in sickle cell anemia.
Medicine (Baltimore) 2014;93:e215.
78. Rana S, Houston PE, Wang WC, et al. Hydroxyurea and growth in young
children with sickle cell disease. Pediatrics 2014;134:465–472.
79. 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;377:1663–1672.
80. Ware RE, Davis BR, Schultz WH, et al. Hydroxycarbamide versus chronic
transfusion for maintenance of transcranial doppler flow velocities in
children with sickle cell anaemia—TCD With Transfusions Changing to
Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority
trial. Lancet 2016;387:661–670.
81. Harmatz P, Butensky E, Quirolo K, et al. Severity of iron overload in patients
with sickle cell disease receiving chronic red blood cell transfusion therapy.
Blood 2000;96:76–79.
82. Miller ST, Kim HY, Weiner DL, et al. Red blood cell alloimmunization in
sickle cell disease: prevalence in 2010. Transfusion 2013; 53:704–709.
83. Telen MJ, Afenyi-Annan A, Garrett ME, et al. Alloimmunization in
sickle cell disease: changing antibody specificities and association with
chronic pain and decreased survival. Transfusion 2015;55(6 Pt 2):
1378–1387.
84. McCavit T, Desai P. Management of Acute Complications of Sickle Cell
Disease: A Pocket Guide for the Clinician. Washington, DC: American
Society of Hematology, 2014.
85. Noronha SA, Lanzkron S. Health Care Maintenace and Management of
Chronic Complications of Sickle Cell Disease: A Pocket Guide for the
Clinician. Washington, DC: American Society of Hematology, 2014.
86. Creary SE, Strouse JJ. Hydroxyurea and Transfusion Therapy for the
Treatment of Sickle Cell Disease: A Pocket Guide for the Clinician.
Washington, DC: American Society of Hematology, 2014.
© 2016 The Southern Medical Association