Consideration of primary prophylaxis to prevent complications of sickle cell disease (SCD) requires a clear understanding of the earliest manifestations of SCD-related organ injury, a reliable clinical or laboratory tool to detect organ dysfunction, and evidence that an intervention instituted in the presymptomatic state can mitigate disease progression. This review examines the pathophysiology of SCD in organs that may be potential targets for intervention, our current capacity to evaluate early SCD manifestations, results of clinical trials, and opportunities for future interventions.

Sickle cell disease (SCD) encompasses inherited anemias due to beta globin mutations that result in the formation of sickled red cells and increased red cell turnover. The complications of SCD are both acute and chronic, and this combination results in significant morbidity, high healthcare utilization over the lifespan, and increased premature death.1  Whereas many avenues have been explored to manage complications of SCD as they arise, renewed attention has been focused on primary prevention before signs of organ dysfunction have appeared, particularly in young children. This review highlights areas of established benefit of primary prophylaxis and emerging data on interventions that may ultimately change the natural history of this condition for patients. Acute and recurrent sickling events ultimately result in organ damage and impaired function. Understanding the pathophysiology and timing of this organ-specific progression, as well as early clinical or laboratory indicators of injury, is necessary to determine: (1) which processes might be amenable to primary prevention, (2) when interventions should take place, and (3) what medications or procedures might be effective. Secondary prophylaxis will only be reviewed as it relates to making a case for intervention in the presymptomatic state. Table 1 provides a summary of the potential targets for primary prophylaxis in SCD.

Table 1.

Potential targets for primary prophylaxis in SCD

Potential targets for primary prophylaxis in SCD
Potential targets for primary prophylaxis in SCD

Spleen

Splenic function is key for maintaining normal immune homeostasis, including opsonization of pathogens such as invasive encapsulated organisms, phagocytic filtration of senescent or damaged cells, and maintenance of lymphocyte subpopulations necessary for both innate and adaptive immune responses.2  Vesicles that accumulate on the RBC surface with age are normally removed by the intact spleen, but these pocked or pitted RBCs remain visible in the circulation in individuals with hyposplenism or asplenia. The developmental patterns of hyposplenism or functional asplenia in SCD were described by Pearson and the other investigators of the Cooperative Study of Sickle Cell Disease (CSSCD) using radionuclide spleen scans and pocked RBC counts.3  A cohort of infants were first evaluated at 8-13 months of age and nearly 69% had pocked RBC counts < 3.5% and simultaneous splenic radio-colloid uptake classified as normal. Those with normal uptake tended to be younger, with higher fetal hemoglobin levels and less anemia. Pocked RBC data on the overall CSSCD population demonstrated that the mean pocked RBC percentages increased most rapidly in the first 6 months of life for individuals with homozygous SCD, somewhat more gradually with the other sickle hemoglobinopathies, and that this timing correlated well with epidemiologic data on the incidence rates of severe bacterial infections. Quantitative detection of Howell-Jolly bodies by flow cytometry has also been used to assess splenic dysfunction. Once autoinfarction of the spleen occurred, it was presumed that splenic function was irreversibly lost.

More recently, the baseline data on splenic function from a larger infant SCD cohort in the Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) found a similar, strong correlation of pocked or pitted RBC counts with liver-spleen scans; however, a much smaller percentage of infants had normal uptake (23%) compared with CCSCD.4  Apparent absent or decreased splenic function was significantly correlated with older age, lower total hemoglobin, lower fetal hemoglobin, and higher WBC. Measurements of Howell-Jolly bodies by flow cytometry were also correlated with the pitted RBC and scintigraphic assessments of splenic function at baseline. By age 12 months, 84% of the infants with SCD in this cohort had decreased or absent splenic uptake.

Kidney

Glomerular hyperfiltration is common in children with SCD. Hyposthenuria and asymptomatic microalbuminuria may be among the earliest signs of renal impairment,5  and limited data suggest that detection of microalbuminuria, defined as urine albumin of 30-300 mg/g of creatinine, predicts the course toward further glomerular injury.6,7  Increased renal plasma flow and intraglomerular hypertension are associated with tubular defects that result in decreased urinary concentrating ability.8  Persistent proteinuria occurs in 6%-12% of pediatric patients with SCD9  as early as 7 years of age, with increasing prevalence into early adulthood.10  Over time, recurrent intrarenal sickling results in sickle nephropathy with features most consistent with focal segmental glomerulosclerosis due to both hyperfiltration and glomerular hypertrophy. SCD-related chronic kidney disease may lead to end-stage renal disease requiring dialysis or transplantation in up to 30% of adults. Well-defined screening and diagnostic tools are needed.

Accurate assessment of the glomerular filtration rate (GFR) is key to identifying opportunities for prevention or early intervention. Estimation of GFR based on the calculated creatinine clearance using the Schwartz or modified cystatin C formula typically overestimates filtration capacity in SCD. Quantitative methods such as inulin clearance or technetium-labeled diethylene-triaminepentaacetic acid (99Tc-DTPA) may be more accurate but may also have limitations in SCD, particularly at the upper end of the range.

The baseline observations of the BABY HUG study included assessment of renal function.11  At study entry, 77.2% of infants at a mean age of 13 months in BABY HUG were able to concentrate urine with controlled fluid deprivation.12  In addition, these young children had scintigraphic GFR measures well above normal for age, suggesting that the renal impairment that leads to glomerular hyperfiltration occurs very early in life. Calculated GFR estimates using the Schwartz equation in general were higher, more variable, and only weakly correlated with renal clearance by 99Tc-DTPA. Quantitated GFR by DTPA in this cohort was correlated with age, height, weight, kidney volume, and decreased serum creatinine, but not with total or fetal hemoglobin. Although a direct progressive relationship of early hyperfiltration to later renal manifestations of SCD has not been fully elucidated, the early onset of impairment is nonetheless concerning and may be an additional target for prophylactic intervention.

Lung

Acute chest syndrome (ACS), which is defined as a new infiltrate on chest radiograph associated with fever and respiratory symptoms (cough, wheezing, and tachypnea), is a leading cause for hospital admissions and deaths in SCD.13  Studies estimate that as many as 90% of adults with SCD have abnormal lung function.14,15  The pathophysiology is complex and includes vasoocclusion due to polymerization of sickle hemoglobin in the relatively hypoxic environment of pulmonary capillaries, hypoxia-related vasoconstriction, release of inflammatory cytokines in response to infection or fat embolism, and endothelial activation with enhanced RBC adhesion.16,17  Restrictive lung disease in adults with SCD is presumed to result from repeated insults during childhood, including ACS.18  Chronic hypoxemia and pulmonary hypertension are additional components of sickle lung disease in adults, however, there are limited data on how they relate to early changes in lung function or structure in young children.

Several longitudinal and cross-sectional studies of lung function in children have demonstrated a progressive decline in lung volumes with early lower airway obstruction, restriction, and airway hyperreactivity.19–22  The bronchodilator response and patterns of cytokine expression in SCD share features with asthma, and suggest that wheezing and obstruction may be manifestations of SCD or of concurrent comorbid states.23  Comprehensive assessment of lung disease typically includes spirometric pulmonary function testing that may not be feasible in younger children. Evaluation of preschool children 2-5 years of age with cystic fibrosis and age-matched normal controls suggest that very young children are capable of completing spirometric studies with motivated, experienced staff.24  To date, there are no published pulmonary function studies in a comparable young SCD cohort. Passive occlusion and nitrogen washout techniques under sedation have been used to obtain limited pulmonary function data on a small, uncontrolled cohort of infants as young as 3 months of age with SCD, and demonstrated findings suggestive of lower airway obstruction and hyperreactivity in some infants.25  It is not clear that this approach is feasible in terms of safety for larger-scale studies or clinical practice, so these data have not yet been reproduced. The feasibility of designing studies to directly address primary prophylaxis for pulmonary complications will require further investigations to identify diagnostic modalities that can be used in the presymptomatic state, likely in very early childhood.

Brain

Cerebrovascular events such as overt strokes occur in 24% of individuals with SCD by the age of 45 years.26  The impact of SCD on the brain has other manifestations as well, including silent cerebral infarcts, altered cerebral vascular flow velocity, and impaired neurocognitive function. The pathologic findings in most but not all cases of overt stroke consist of intimal thickening in medium to large intracranial blood vessels likely due to recurrent sickling-induced endothelial injury with thrombosis.27  Silent cerebral infarcts, high-signal MRI abnormalities in the absence of overt neurological signs, are detectable in 20%-35% of children28  and are a risk factor for overt stroke and cognitive impairment. Studies performed on infants at the initiation of the BABY HUG study identified silent cerebral infarcts in 13% at a median age of 13.7 months, suggesting that the brain injury represented by these lesions occurs at a very early age.29  Altered cerebral blood flow due to severe anemia and/or stenosis may be manifested by elevated flow velocity shown by transcranial Doppler (TCD). Approximately 10% of children in the Stroke Prevention Trial in Sickle Cell Anemia (STOP) had velocities in the abnormal range, most often in children 2-8 years of age.30  Baseline data from the BABY HUG trial identified no patients at a mean age of 12.6 months with abnormal TCDs,31  providing a potential window of opportunity for early intervention.

Penicillin

The efficacy of oral penicillin as primary prophylaxis in SCD was clearly demonstrated in pivotal trials published nearly 25 years ago.32,33  In a study by Gaston et al, children who were randomized to the daily oral penicillin prophylaxis arm of the study had an 85% reduction in the probability of infection compared with those given placebo. This study provided much-needed impetus for states in the United States to adopt universal newborn testing to ensure that all children with SCD were identified, with a strong recommendation for prompt penicillin initiation.34  The clear benefit of newborn screening combined with penicillin prophylaxis is demonstrated by decreases in SCD-related mortality among black children under the age of 4 years by 68% from 1983-1986 to 1999-2002, with the largest decrease occurring after 2000, when the 7-valent pneumococcal vaccine was added to the schedule of recommended immunizations for all children.35,36  Similar improvements in survival were noted in the Dallas Newborn Cohort, in which all children identified through newborn screening were immunized, given penicillin prophylaxis at least through the age of 5 years, and provided with comprehensive medical care.37,38  The proportion of children surviving to age 18 years was 93.9%, and sepsis was no longer the leading cause of deaths.

A follow-up study to determine acceptable circumstances for discontinuation of penicillin was restricted to fully immunized children with homozygous sickle cell and sickle beta zero thalassemia who had been compliant with penicillin, had no serious infections in the first 5 years of life, and were not splenectomized.39  Episodes of pneumococcal infections occurred at lower rates than anticipated in both arms of this randomized, double-blind, placebo-controlled study. Because no significant difference could be detected, the investigators concluded that penicillin prophylaxis could be safely discontinued at age 5 years, although some pediatric hematologists continue to recommend indefinite prophylaxis given concerns about infection susceptibility.40  Subsequent studies examining invasive pneumococcal infections at regional pediatric SCD programs in the era of penicillin prophylaxis, immunization with the 23-valent pneumococcal vaccine in children with SCD, and the addition of the 7-valent–conjugated pneumococcal vaccine to the standard schedule in all children have demonstrated benefits in survival and infection rates.41,42 

Hydroxyurea

Hydroxyurea is a well-characterized pharmacologic agent initially used as an antineoplastic drug that inhibited ribonucleotide reductase in DNA synthesis. Because hydroxyurea use was associated with an increase in HbF, and mechanistically because endogenous or induced fetal hemoglobin elevation is known to reduce the severity of SCD, hydroxyurea became a focus of translational and clinical research in SCD. Hydroxyurea-induced marrow suppression favors proliferation of RBC precursors containing HbF. Overall hemoglobin content is increased and hydroxyurea improves sickle RBC hydration and reduces RBC adherence to endothelial cells. The chronology of pivotal clinical trials of hydroxyurea and related observations was eloquently summarized by Ware and Aygun.43  The phase 3 randomized Multicenter Study of Hydroxyurea (MSH) trial in adults with SCD established the efficacy of hydroxyurea in reducing pain severity and frequency of hospitalizations for pain management, and also showed a decrease in ACS among participants taking hydroxyurea.44  A small open-label pilot study of severely affected children with SCD suggested that hydroxyurea was associated with a reduction in the length and frequency of admissions.45  These observations were extended to severely affected children 5-15 years of age in the phase 1/2 HUG-KIDS study, which demonstrated both safety and efficacy in this age cohort.46  A systematic review of hydroxyurea in children with SCD was commissioned by the National Institutes of Health Office of Medical Applications of Research to determine the strength of evidence on its efficacy, toxicity, and effectiveness.47  Whereas the efficacy of hydroxyurea to induce fetal hemoglobin and reduce hospital admissions was strong, evidence of its benefit in preserving splenic function was considered low.

The impact of hydroxyurea on the prevention of microalbuminuria or the progression of renal dysfunction in asymptomatic children has been suggested by some small observational studies.5,48  In general, children without microalbuminuria who were treated with hydroxyurea for nonrenal clinical manifestations of SCD did not develop microalbuminuria, and some who had microalbuminuria when hydroxyurea was initiated did not worsen. The combined use of hydroxyurea with an ACE inhibitor such as enalapril resulted in reduced urinary protein excretion and improved creatinine clearance.

Reports on the capacity of hydroxyurea to impact splenic function in SCD in severely affected older children have shown variable responses.49–52  The first clinical trial designed specifically to study hydroxyurea for primary prophylaxis in SCD came with the Hydroxyurea Safety and Organ Toxicity (HU-SOFT) trial.53  This prospective, open-label, multicenter study sought to determine the feasibility of administering hydroxyurea to very young children (median age 15 months) while assessing toxicity, hematologic responses, and retention of splenic function. Hydroxyurea was well tolerated and had acceptable short-term toxicity in this fixed-dose, 2-year study. Among children with liver-spleen scans performed at both study entry and exit, most had unchanged or reduced splenic uptake over time. Splenic uptake was absent at the end of the study period for 47% of HU-SOFT participants, which compared favorably to children in the Cooperative Study of Sickle Cell Disease, in which 78% of children had pitted RBC counts > 3.5% by the age of 3 years.54  An extended study with dose escalation continued to demonstrate hematologic responses with increased fetal hemoglobin, normal growth, and no novel toxicities.55  In examining those subjects with serial assessments of splenic function, 21.5% had normal uptake after a mean duration of 4.9 years on hydroxyurea, whereas 43% at extension exit had absent splenic uptake, at an age when the majority of children with homozygous sickle cell historically were presumed to have functional asplenia.

These data created a strong scientific basis for the design of the BABY HUG trial. In this multicenter, double-blind, placebo-controlled trial, 193 young children, 9-18 months of age with homozygous sickle cell or sickle beta zero thalassemia were randomized to receive or not receive hydroxyurea at a fixed dose. The primary end points for this study were reduction in the decline of splenic function measured by liver-spleen scan by 50% with hydroxyurea and attenuation of the increase in glomerular filtration based on 99Tc-DTPA clearance.56  Secondary end points included comparison of liver spleen scans with other laboratory assessments of splenic function, the utility of calculated estimates of GFR for determining renal function, and investigations of growth, neurodevelopment, and mutagenesis. Adverse events, including expected SCD manifestations, potential treatment toxicities, and serious unanticipated events, were also evaluated.

With greater numbers of infants at study entry having diminished splenic uptake and altered glomerular filtration than reported in previous studies, BABY HUG did not detect significant improvements over the study period in either renal or splenic function with hydroxyurea compared with placebo, and therefore the study failed to meet the primary study end points.57  There are several potential explanations for these findings. As with previous studies on hydroxyurea in very young children, a fixed dose schedule (20 mg/kg) was used, presumably to abrogate toxicity. Greater impact on organ function might have been achieved had the study design allowed for dose escalation. Furthermore, the decline in splenic function in the placebo group was smaller than expected, and therefore the relative difference with the hydroxyurea may have been less significant. It is unclear if the manner in which the assays were used, such as the qualitative interpretation of the splenic uptake, adversely affected the study outcome or if there is in fact no true benefit to hydroxyurea prophylaxis in this setting. In prior studies, interpretation of scintigraphic studies (“normal” versus “present but reduced”) may have not been comparable to BABY HUG, creating study design challenges. The duration of the core study may not have been adequate to detect significant changes, and the imposition of a 3-month clinical hold on drug distribution may have also had some effect. It is also conceivable that with a longer observation period, as proposed in the BABY HUG follow-up, open-label extension study, other clinical benefits will accrue.

Despite the limitations of BABY HUG to demonstrate direct benefit of hydroxyurea as primary prophylaxis, the study makes important contributions to our understanding of the pathophysiology of early disease manifestations, which might be further explored in future studies. As secondary end points, the study found reductions in the frequency of pain episodes and ACS and fewer hospitalizations for subjects who received hydroxyurea compared with controls, findings that have been associated with reduced early mortality in other SCD studies. As seen in most studies of hydroxyurea in SCD, there were significant changes in laboratory parameters, such as increased total hemoglobin and fetal hemoglobin and lower WBC counts in participants who received hydroxyurea on BABY HUG, without excess or novel toxicities. The relationship of these findings to improved long-term outcomes, including reduced mortality, has been demonstrated in other SCD trials,55,58  but this is beyond the stated objectives of the BABY HUG study.

Transfusion

Relief of anemia, relative reductions in the percentage of circulating RBCs, high intracellular concentrations of sickle hemoglobin, and relative improvements in oxygen-carrying capacity are the most common goals for acute or chronic RBC transfusions. Chronic transfusions at present are the most effective intervention to prevent recurrent cerebrovascular events in SCD patients who have had overt strokes. Transfusion for primary prevention in children with SCD and elevated blood flow velocities in major cerebral blood vessels was demonstrated in the STOP trial.30  This study demonstrated a 90% reduction in risk of stroke in the transfusion group, leading to the recommendation that all SCD children 2-16 years of age have an annual screening TCD, and that chronic transfusions be initiated in those with documented abnormal velocities. The effectiveness of TCD screening and primary intervention has now been demonstrated by 2 large independent comprehensive SCD programs, with significant reductions (3- to 10-fold) in overt stroke incidences since starting routine screening with TCD.59,60 

SCD complications among the infant cohort from the CCSCD were examined to create a model to predict adverse outcomes by the age of 10 years.61  Children with severe anemia (hemoglobin < 7 g/dL), early dactylitis (< 1 year of age), and leukocytosis were more likely to have severe disease manifestations such as stroke, recurrent pain, or ACS. The presence of > 3.5% pocked RBCs at 1 year of age was also a significant predictor of adverse outcomes, but was not available for all participants. This model was validated retrospectively; however, a more recent application of these predictors to an independent cohort could not reproduce these findings.62 

New biomarkers of kidney injury may be useful in predicting sickle nephropathy. Urine kidney injury molecule 1 (KIM-1) and N-acetyl-b-D-glucosaminidase (NAG) are strongly correlated with increasing microalbuminuria and proteinuria with age in SCD.63  Serum cystatin C, which has been used as a marker of renal dysfunction in a variety of clinical conditions, is inversely correlated with DTPA GFR, and thus may be an early marker of SCD-related hyperfiltration.64 

Gene-association studies may be useful in focusing on certain aspects of disease pathophysiology that might be exploited in new primary prevention strategies, or they may aid in the prediction of which patients are likely to respond to an intervention. The phenotypic heterogeneity of SCD is likely the result of modifying genes. The best examples of genetic modifiers in SCD are regulators of fetal hemoglobin production and coinheritance of alpha thalassemia.65,66  The XmnI polymorphism in the gamma globin promoter, the HBS1-MYB intergenic sequences, and BCL11A account for 20%-50% of the variations in fetal hemoglobin levels in SCD,67  and may be targets for new therapies in the future and potential markers to incorporate into the design of future prophylaxis studies.

Penicillin prophylaxis and transfusions in children at high risk of strokes are prime examples of the feasibility and effectiveness of early intervention. Primary prevention as a strategy to reduce morbidity and mortality due to other SCD-related complications remains elusive. Recent studies continue to define the natural history of SCD and new opportunities for intervention. Enhanced knowledge of disease pathophysiology and the development of clinical tools to accurately assess early manifestations of organ dysfunction are of vital importance and currently limit the feasibility of interventions specifically focused on primary prevention. The correlation of splenic biomarkers with absent splenic function on liver-spleen scans in very young children with SCD provides a framework for future studies. More longitudinal studies with validated tools to assess renal and pulmonary changes over time in SCD are needed to link manifestations during childhood to later progressive organ injury. Hydroxyurea continues to show benefit in reducing pain and ACS across the lifespan, and its more widespread use for these indications should be pursued; however, its role in preventing organ dysfunction needs further investigation. Ongoing engagement of researchers and the SCD community to launch and successfully complete clinical trials will be essential. Opportunities for future studies that focus on the prevention of SCD complications may ultimately improve survival and quality of life for these patients.

Conflict-of-interest disclosure: The author declares no competing financial interests. Off-label drug use: Hydroxyurea is FDA-approved for use only in adult SCD patients.

Alexis A. Thompson, MD, MPH, Division of Hematology, Oncology & Stem Cell Transplant, Children's Memorial Hospital, Box 30, 2300 Children's Plaza, Chicago, IL 60614; Phone: (773) 880-4562; Fax: (773) 880-3223; e-mail: a-thompson@northwestern.edu.

1
Powars
 
DR
Chan
 
LS
Hiti
 
A
Ramicone
 
E
Johnson
 
C
Outcome of sickle cell anemia: a 4-decade observational study of 1056 patients
Medicine (Baltimore)
2005
, vol. 
84
 (pg. 
363
-
376
)
2
Di Sabatino
 
A
Carsetti
 
R
Corazza
 
GR
Post-splenectomy and hyposplenic states
Lancet
2011
, vol. 
378
 
9785
(pg. 
86
-
97
)
3
Pearson
 
HA
Gallagher
 
D
Chilcote
 
R
, et al. 
Developmental pattern of splenic dysfunction in sickle cell disorders
Pediatrics
1985
, vol. 
76
 (pg. 
392
-
397
)
4
Rogers
 
ZR
Wang
 
WC
Luo
 
Z
, et al. 
Biomarkers of splenic function in infants with sickle cell anemia: baseline data from the BABY HUG Trial
Blood
2011
, vol. 
117
 (pg. 
2614
-
2617
)
5
McKie
 
KT
Hanevold
 
CD
Hernandez
 
C
Waller
 
JL
Ortiz
 
L
McKie
 
KM
Prevalence, prevention, and treatment of microalbuminuria and proteinuria in children with sickle cell disease
J Pediatr Hematol Oncol
2007
, vol. 
29
 (pg. 
140
-
144
)
6
Guasch
 
A
Cua
 
M
Mitch
 
WE
Early detection and the course of glomerular injury in patients with sickle cell anemia
Kidney Int
1996
, vol. 
49
 (pg. 
786
-
791
)
7
Datta
 
V
Ayengar
 
JR
Karpate
 
S
Chaturvedi
 
P
Microalbuminuria as a predictor of early glomerular injury in children with sickle cell disease
Indian J Pediatr
2003
, vol. 
70
 (pg. 
307
-
309
)
8
Scheinman
 
JI
Sickle cell disease and the kidney
Nat Clin Pract Nephrol
2009
, vol. 
5
 (pg. 
78
-
88
)
9
Wigfall
 
DR
Ware
 
RE
Burchinal
 
MR
Kinney
 
TR
Foreman
 
JW
Prevalence and clinical correlates of glomerulopathy in children with sickle cell disease
J Pediatr
2000
, vol. 
136
 (pg. 
749
-
753
)
10
Ataga
 
KI
Orringer
 
EP
Renal abnormalities in sickle cell disease
Am J Hematol
2000
, vol. 
63
 (pg. 
205
-
211
)
11
Ware
 
RE
Rees
 
RC
Sarnaik
 
SA
, et al. 
Renal function in infants with sickle cell anemia: baseline data from the BABY HUG trial
J Pediatr
2010
, vol. 
156
 (pg. 
66
-
70
)
12
Miller
 
ST
Wang
 
WC
Iyer
 
R
, et al. 
Urine concentrating ability in infants with sickle cell disease: baseline data from the phase III trial of hydroxyurea (BABY HUG)
Pediatr Blood Cancer
2010
, vol. 
54
 (pg. 
265
-
268
)
13
Vichinsky
 
EP
Styles
 
LA
Colangelo
 
LH
Wright
 
EC
Castro
 
O
Nickerson
 
B
Acute chest syndrome in sickle cell disease: clinical presentation and course. Cooperative Study of Sickle Cell Disease
Blood
1997
, vol. 
89
 (pg. 
1787
-
1792
)
14
Klings
 
ES
Wyszynski
 
DF
Nolan
 
VG
Steinberg
 
MH
Abnormal pulmonary function in adults with sickle cell anemia
Am J Respir Crit Care Med
2006
, vol. 
173
 (pg. 
1264
-
1269
)
15
Field
 
JJ
Glassberg
 
J
Gilmore
 
A
, et al. 
Longitudinal analysis of pulmonary function in adults with sickle cell disease
Am J Hematol
2008
, vol. 
83
 (pg. 
574
-
576
)
16
Stuart
 
MJ
Nagel
 
RL
Sickle-cell disease
Lancet
2004
, vol. 
364
 (pg. 
1343
-
1360
)
17
Hebbel
 
RP
Osarogiagbon
 
R
Kaul
 
D
The endothelial biology of sickle cell disease: inflammation and a chronic vasculopathy
Microcirculation
2004
, vol. 
11
 (pg. 
129
-
151
)
18
Knight-Madden
 
JM
Forrester
 
TS
Lewis
 
NA
Greenough
 
A
The impact of recurrent acute chest syndrome on the lung function of young adults with sickle cell disease
Lung
2010
, vol. 
188
 (pg. 
499
-
504
)
19
MacLean
 
JE
Atenafu
 
E
Kirby-Allen
 
M
, et al. 
Longitudinal decline in lung volume in a population of children with sickle cell disease
Am J Respir Crit Care Med
2008
, vol. 
178
 (pg. 
1055
-
1059
)
20
Koumbourlis
 
AC
Zar
 
HJ
Hurlet-Jensen
 
A
Goldberg
 
MR
Prevalence and reversibility of lower airway obstruction in children with sickle cell disease
J Pediatr
2001
, vol. 
138
 (pg. 
188
-
192
)
21
Sylvester
 
KP
Patey
 
RA
Milligan
 
P
, et al. 
Pulmonary function abnormalities in children with sickle cell disease
Thorax
2004
, vol. 
59
 (pg. 
67
-
70
)
22
Boyd
 
JH
DeBaun
 
MR
Morgan
 
WJ
Mao
 
J
Strunk
 
RC
Lower airway obstruction is associated with increased morbidity in children with sickle cell disease
Pediatr Pulmonol
2009
, vol. 
44
 (pg. 
290
-
296
)
23
Field
 
JJ
DeBaun
 
MR
Asthma and sickle cell disease: two distinct diseases or part of the same process?
Hematology Am Soc Hematol Educ Program
2009
(pg. 
45
-
53
)
24
Aurora
 
P
Stocks
 
J
Oliver
 
C
, et al. 
Quality control for spirometry in preschool children with and without lung disease
Am J Respir Crit Care Med
2004
, vol. 
169
 (pg. 
1152
-
1159
)
25
Koumbourlis
 
AC
Hurlet-Jensen
 
A
Bye
 
MR
Lung function in infants with sickle cell disease
Pediatr Pulmonol
1997
, vol. 
24
 (pg. 
277
-
281
)
26
Ohene-Frempong
 
K
Weiner
 
SJ
Sleeper
 
LA
, et al. 
Cerebrovascular accidents in sickle cell disease: rates and risk factors
Blood
1998
, vol. 
91
 (pg. 
288
-
294
)
27
Switzer
 
JA
Hess
 
DC
Nichols
 
FT
Adams
 
RJ
Pathophysiology and treatment of stroke in sickle-cell disease: present and future
Lancet Neurol
2006
, vol. 
5
 (pg. 
501
-
512
)
28
Kwiatkowski
 
JL
Zimmerman
 
RA
Pollock
 
AN
, et al. 
Silent infarcts in young children with sickle cell disease
Br J Haematol
2009
, vol. 
146
 (pg. 
300
-
305
)
29
Wang
 
WC
Pavlakis
 
SG
Helton
 
KJ
, et al. 
MRI abnormalities of the brain in one-year-old children with sickle cell anemia
Pediatr Blood Cancer
2008
, vol. 
51
 (pg. 
643
-
646
)
30
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
, vol. 
339
 (pg. 
5
-
11
)
31
Pavlakis
 
SG
Rees
 
RC
Huang
 
X
, et al. 
Transcranial doppler ultrasonography (TCD) in infants with sickle cell anemia: baseline data from the BABY HUG trial
Pediatr Blood Cancer
2010
, vol. 
54
 (pg. 
256
-
259
)
32
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
, vol. 
314
 (pg. 
1593
-
1599
)
33
John
 
AB
Ramlal
 
A
Jackson
 
H
Maude
 
GH
Sharma
 
AW
Serjeant
 
GR
Prevention of pneumococcal infection in children with homozygous sickle cell disease
Br Med J (Clin Res Ed)
1984
, vol. 
288
 (pg. 
1567
-
1570
)
34
Consensus conference
Newborn screening for sickle cell disease and other hemoglobinopathies
JAMA
1987
, vol. 
258
 (pg. 
1205
-
1209
)
35
Halasa
 
NB
Shankar
 
SM
Talbot
 
TR
, et al. 
Incidence of invasive pneumococcal disease among individuals with sickle cell disease before and after the introduction of the pneumococcal conjugate vaccine
Clin Infect Dis
2007
, vol. 
44
 (pg. 
1428
-
1433
)
36
Yanni
 
E
Grosse
 
SD
Yang
 
Q
Olney
 
RS
Trends in pediatric sickle cell disease-related mortality in the United States, 1983-2002
J Pediatr
2009
, vol. 
154
 (pg. 
541
-
545
)
37
Quinn
 
CT
Rogers
 
ZR
Buchanan
 
GR
Survival of children with sickle cell disease
Blood
2004
, vol. 
103
 (pg. 
4023
-
4027
)
38
Quinn
 
CT
Rogers
 
ZR
McCavit
 
TL
Buchanan
 
GR
Improved survival of children and adolescents with sickle cell disease
Blood
2010
, vol. 
115
 (pg. 
3447
-
3452
)
39
Falletta
 
JM
Woods
 
GM
Verter
 
JI
, et al. 
Discontinuing penicillin prophylaxis in children with sickle cell anemia. Prophylactic Penicillin Study II
J Pediatr
1995
, vol. 
127
 (pg. 
685
-
690
)
40
Riddington
 
C
Owusu-Ofori
 
S
Prophylactic antibiotics for preventing pneumococcal infection in children with sickle cell disease
Cochrane Database Syst Rev
2002
pg. 
CD003427
 
41
Hord
 
J
Byrd
 
R
Stowe
 
L
Windsor
 
B
Smith-Whitley
 
K
Streptococcus pneumoniae sepsis and meningitis during the penicillin prophylaxis era in children with sickle cell disease
J Pediatr Hematol Oncol
2002
, vol. 
24
 (pg. 
470
-
472
)
42
Adamkiewicz
 
TV
Sarnaik
 
S
Buchanan
 
GR
, et al. 
Invasive pneumococcal infections in children with sickle cell disease in the era of penicillin prophylaxis, antibiotic resistance, and 23-valent pneumococcal polysaccharide vaccination
J Pediatr
2003
, vol. 
143
 (pg. 
438
-
444
)
43
Ware
 
RE
Aygun
 
B
Advances in the use of hydroxyurea
Hematology Am Soc Hematol Educ Program
2009
(pg. 
62
-
69
)
44
Charache
 
S
Terrin
 
ML
Moore
 
RD
, et al. 
Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia
N Engl J Med
1995
, vol. 
332
 (pg. 
1317
-
1322
)
45
Scott
 
JP
Hillery
 
CA
Brown
 
ER
Misiewicz
 
V
Labotka
 
RJ
Hydroxyurea therapy in children severely affected with sickle cell disease
J Pediatr
1996
, vol. 
128
 (pg. 
820
-
828
)
46
Kinney
 
TR
Helms
 
RW
O'Branski
 
EE
, et al. 
Safety of hydroxyurea in children with sickle cell anemia: results of the HUG-KIDS study, a phase I/II trial. Pediatric Hydroxyurea Group
Blood
1999
, vol. 
94
 (pg. 
1550
-
1554
)
47
Strouse
 
JJ
Lanzkron
 
S
Beach
 
MC
, et al. 
Hydroxyurea for sickle cell disease: a systematic review for efficacy and toxicity in children
Pediatrics
2008
, vol. 
122
 (pg. 
1332
-
1342
)
48
Fitzhugh
 
CD
Wigfall
 
DR
Ware
 
RE
Enalapril and hydroxyurea therapy for children with sickle nephropathy
Pediatr Blood Cancer
2005
, vol. 
45
 (pg. 
982
-
985
)
49
Olivieri
 
NF
Vichinsky
 
EP
Hydroxyurea in children with sickle cell disease: impact on splenic function and compliance with therapy
J Pediatr Hematol Oncol
1998
, vol. 
20
 (pg. 
26
-
31
)
50
Claster
 
S
Vichinsky
 
E
First report of reversal of organ dysfunction in sickle cell anemia by the use of hydroxyurea: splenic regeneration
Blood
1996
, vol. 
88
 (pg. 
1951
-
1953
)
51
Santos
 
A
Pinheiro
 
V
Anjos
 
C
, et al. 
Scintigraphic follow-up of the effects of therapy with hydroxyurea on splenic function in patients with sickle cell disease
Eur J Nucl Med Mol Imaging
2002
, vol. 
29
 (pg. 
536
-
541
)
52
Hankins
 
JS
Helton
 
KJ
McCarville
 
MB
Li
 
CS
Wang
 
WC
Ware
 
RE
Preservation of spleen and brain function in children with sickle cell anemia treated with hydroxyurea
Pediatr Blood Cancer
2008
, vol. 
50
 (pg. 
293
-
297
)
53
Wang
 
WC
Wynn
 
LW
Rogers
 
ZR
Scott
 
JP
Lane
 
PA
Ware
 
RE
A two-year pilot trial of hydroxyurea in very young children with sickle-cell anemia
J Pediatr
2001
, vol. 
139
 (pg. 
790
-
796
)
54
Brown
 
AK
Sleeper
 
LA
Miller
 
ST
Pegelow
 
CH
Gill
 
FM
Waclawiw
 
MA
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
, vol. 
148
 (pg. 
796
-
804
)
55
Hankins
 
JS
Ware
 
RE
Rogers
 
ZR
, et al. 
Long-term hydroxyurea therapy for infants with sickle cell anemia: the HUSOFT extension study
Blood
2005
, vol. 
106
 (pg. 
2269
-
2275
)
56
Thompson
 
BW
Miller
 
ST
Rogers
 
ZR
, et al. 
The pediatric hydroxyurea phase III clinical trial (BABY HUG): challenges of study design
Pediatr Blood Cancer
2010
, vol. 
54
 (pg. 
250
-
255
)
57
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
, vol. 
377
 (pg. 
1663
-
1672
)
58
Zimmerman
 
SA
Schultz
 
WH
Davis
 
JS
, et al. 
Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease
Blood
2004
, vol. 
103
 (pg. 
2039
-
2045
)
59
McCarville
 
MB
Goodin
 
GS
Fortner
 
G
, et al. 
Evaluation of a comprehensive transcranial doppler screening program for children with sickle cell anemia
Pediatr Blood Cancer
2008
, vol. 
50
 (pg. 
818
-
821
)
60
Enninful-Eghan
 
H
Moore
 
RH
Ichord
 
R
Smith-Whitley
 
K
Kwiatkowski
 
JL
Transcranial Doppler ultrasonography and prophylactic transfusion program is effective in preventing overt stroke in children with sickle cell disease
J Pediatr
2010
, vol. 
157
 (pg. 
479
-
484
)
61
Miller
 
ST
Sleeper
 
LA
Pegelow
 
CH
, et al. 
Prediction of adverse outcomes in children with sickle cell disease
N Engl J Med
2000
, vol. 
342
 (pg. 
83
-
89
)
62
Quinn
 
CT
Lee
 
NJ
Shull
 
EP
Ahmad
 
N
Rogers
 
ZR
Buchanan
 
GR
Prediction of adverse outcomes in children with sickle cell anemia: a study of the Dallas Newborn Cohort
Blood
2008
, vol. 
111
 (pg. 
544
-
548
)
63
Sundaram
 
N
Bennett
 
M
Wilhelm
 
J
, et al. 
Biomarkers for early detection of sickle nephropathy
Am J Hematol
2011
, vol. 
86
 
7
(pg. 
559
-
566
)
64
Aygun
 
B
Mortier
 
NA
Smeltzer
 
MP
Hankins
 
JS
Ware
 
RE
Glomerular hyperfiltration and albuminuria in children with sickle cell anemia
Pediatr Nephrol
2011
, vol. 
26
 
8
(pg. 
1285
-
1290
)
65
Rees
 
DC
Williams
 
TN
Gladwin
 
MT
Sickle-cell disease
Lancet
2010
, vol. 
376
 (pg. 
2018
-
2031
)
66
Steinberg
 
MH
Predicting clinical severity in sickle cell anaemia
Br J Haematol
2005
, vol. 
129
 (pg. 
465
-
481
)
67
Thein
 
SL
Menzel
 
S
Lathrop
 
M
Garner
 
C
Control of fetal hemoglobin: new insights emerging from genomics and clinical implications
Hum Mol Genet
2009
, vol. 
18
 (pg. 
R216
-
R223
)