prognostic significance of early vaso-occlusive complications in children with sickle cell anemia
TRANSCRIPT
QUINN et al. Significance of Early Vaso-Occlusive Complications
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Prognostic significance of early vaso-occlusive complications in children
with sickle cell anemia
Charles T. Quinn,1,2,3 Elizabeth P. Shull,2,3 Naveed Ahmad,3 Nancy J. Lee,2,3
Zora R. Rogers,1,2,3 and George R. Buchanan.1,2,3
From the 1Division of Hematology-Oncology, Department of Pediatrics, University
of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA; 2Southwestern Comprehensive Sickle Cell Center, Dallas, TX, USA; and 3Children’s Medical Center Dallas, Dallas, TX, USA.
Supported partly by a grant from the National Institutes of Health (U54 HL 70588)
Charles T. Quinn, M.D.
U.T. Southwestern Medical Center
5323 Harry Hines Blvd.
Dallas, TX 75390-9063
Phone: 214-648-3896, Fax: 214-648-3122
Email: [email protected].
Abstract word count: 194
Body word count: 4,100
Short title: Significance of Early Vaso-Occlusive Complications
Keywords: sickle cell disease, risk factors, outcomes, vaso-occlusive crisis, acute
chest syndrome, dactylitis, children.
Statement of Authors’ Contributions: CTQ designed the research, oversaw the
data collection, assisted in the statistical analysis, and wrote the manuscript. EPS
and NJL collected and maintained the data. NA provided statistical services and
assistance writing the manuscript. ZR and GB provided project oversight,
feedback, and assistance writing the manuscript.
Blood First Edition Paper, prepublished online August 29, 2006; DOI 10.1182/blood-2006-02-005082
Copyright © 2006 American Society of Hematology
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QUINN et al. Significance of Early Vaso-Occlusive Complications
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ABSTRACT
Sickle cell anemia (SS) is highly phenotypically variable, and early predictors of
outcome could guide clinical care. To determine whether early vaso-occlusive
complications predicted subsequent adverse outcomes in the Dallas Newborn
Cohort, we studied all members with SS or sickle-β0-thalassemia who presented
in their first year of life and had ≥5 years of follow-up. We defined three potential
early predictors: hospitalizations in the first 3 years of life for (1) painful events
other than dactylitis, (2) dactylitis, and (3) acute chest syndrome (ACS). We
studied the associations of these predictors with the following late adverse
outcomes (occurring after the third birthday): death; first overt stroke; use of
disease-modifying therapy; and hospitalizations for pain events and ACS. None
of the early events predicted death or stroke. Early pain and ACS both predicted
a modest, temporary increase in the number of later painful episodes, but early
ACS strongly increased the odds of more frequent ACS throughout childhood.
Dactylitis had limited utility as a predictor. Although we still lack a useful
prognostic framework for young children with SS, those who experience early
ACS might be candidates for higher risk interventions to mitigate or cure their
disease.
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INTRODUCTION
Homozygous sickle cell anemia (SS) is the most severe form of sickle cell
disease (SCD), but it is phenotypically variable, and the course of disease is
difficult to predict.1 Some individuals with SS have frequent vaso-occlusive
complications and die prematurely,2,3 while others have few problems and a
normal lifespan.4,5 Many genes both within and outside the beta globin locus
modify the phenotype of SS, but we have only a limited understanding of a few
such genotype-phenotype interactions.6,7
The prediction in very early childhood of later severe disease would permit risk-
based counseling for families and could justify the early use of disease-modifying
or curative interventions, such as hydroxyurea (HU), chronic transfusions (CT), or
stem cell transplantation (SCT). The hazards of these treatments vary greatly,
especially in comparison with preventive and supportive management alone.8
Accurate and reliable early predictors would provide the opportunity to better
balance the risks of these interventions with risks of the disease itself.
Vaso-occlusive complications have been studied as predictors of SCD severity.
Platt and colleagues reported for the Cooperative Study of Sickle Cell Disease
(CSSCD) that the rate of pain—itself a measure of clinical disease severity—
correlated with early mortality in adults.3 Likewise, Miller and colleagues for the
CSSCD showed that children who, in the first year of life, experienced dactylitis,
a painful vaso-occlusive complication of SCD, were more likely to have adverse
outcomes in later childhood, including death, stroke, frequent pain, and recurrent
ACS.9 This finding from the multi-center CSSCD infant cohort has not been
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confirmed in other cohorts. The prognostic significance of ACS and painful
episodes other than dactylitis in early childhood is not known.
We sought to test the assumption of many clinicians that children who
experienced vaso-occlusive complications in very early life, not limited to
dactylitis, were destined to have severe SCD in later childhood. To this end, we
studied the Dallas Newborn Cohort10 to determine if hospitalizations for painful
events, dactylitis, or ACS during the first three years of life were associated with
death, stroke, or other measures of severe disease between 3 and 20 years of
age. We hypothesized that hospitalizations for early vaso-occlusive
complications did not clearly predict later adverse outcomes.
PATIENTS AND METHODS
Cohort Members
This is a retrospective analysis of the Dallas Newborn Cohort,10 whose members
are tracked prospectively in our center’s comprehensive sickle cell disease
database. This newborn inception cohort includes the four common SCD
genotypes: SS, sickle-hemoglobin C disease (SC), sickle-β0-thalassemia (Sβ0),
and sickle-β+-thalassemia (Sβ+). It is unique among SCD cohorts because State
newborn screening for hemoglobinopathies identified all members, and all
subjects with SS or Sβ0 were prescribed prophylactic penicillin until at least 5
years of age. Accrual began in 1983 and is ongoing. The Cohort now includes
826 subjects and provides 7,275 patient-years of observation. This analysis
includes follow-up through July 13, 2005.
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We studied every member of the Cohort who was less than 20 years of age, who
had a diagnosis of either SS or Sβ0, whose first visit to our center was in the first
year of life, who were at least 5 years of age at the time of their last clinical
encounter in our center, and who had complete records available for review. The
percentage subjects who were lost-to-follow-up in the entire Cohort was 3.5%.10
We studied individuals with SS and Sβ0 as a single group because of the known
clinical similarity of the diseases, the very small number in the Sβ0 subgroup, and
the difficulty differentiating the two diseases using standard clinical and
laboratory assessments. The Institutional Review Board of UT Southwestern
approved the use of the clinical database for this project.
Early Predictors
We defined “early” vaso-occlusive complications to be those that occurred during
the first three years of life (before the third birthday). We defined this cut-off
before the data were collected and analyzed, and we chose it because pain
events other than dactylitis and ACS are uncommon in the first year of life.
Further, two additional years of “early” follow-up would provide a larger number
of early vaso-occlusive complications to study as predictors. This definition is
also clinically meaningful, because it permitted us to study early disease
manifestations before most irreversible organ damage, other than splenic
dysfunction, was likely to have occurred in most children.
We defined three potential “early” vaso-occlusive predictors: (1) hospitalization
for a painful episode (excluding dactylitis), (2) hospitalization for dactylitis, and (3)
hospitalization for ACS. These predictors were chosen because they are
common, clinically overt manifestations of SCD whose occurrence currently
informs clinical decision-making. We studied only inpatient episodes because of
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the design of our clinical database: we systematically track the discharge
diagnoses for all subjects’ hospitalizations but not outpatient painful events. Early
hospitalizations were identified by query of the database and review of selected
medical records, and they were categorized by the subject’s age at the time of
occurrence. Reasons for hospitalization (discharge diagnoses) had been
recorded at the time of each event. If the reason for any single hospitalization
was recorded in the database as both painful event and ACS (e.g., painful event
complicated by ACS), the hospitalization was counted as an episode of ACS only
(because ACS was considered to be the more severe complication). In our
clinical practice, we have defined ACS as an acute pulmonary illness in a person
who has SCD that is characterized by a new radiographic pulmonary infiltrate
and some combination of fever, hypoxemia, thoracic pain, and signs and
symptoms of respiratory illness.
Late Outcomes
We studied the associations of these early predictors with the following “late”
outcomes: (1) a death of any cause; (2) a clinically overt first stroke; (3) the use
of hydroxyurea (HU), chronic transfusions (CT), or stem cell transplantation
(SCT); (4) the number and rate of hospitalization for painful episodes; and (5) the
number and rate of hospitalization for ACS. By definition, all “late” outcomes
occurred on or after the third birthday. These outcomes were identified by query
of the database and review of selected medical records, and they were
categorized by the subject’s age at the time of occurrence. If the reason for any
single hospitalization was recorded as both painful event and ACS, the
hospitalization was counted as an episode of ACS only. Events up to age 20
years were included.
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To quantify late pain and ACS, we recorded all subjects’ hospitalizations for late
pain and ACS that occurred on or after the third birthday through the last clinical
encounter or the start date of a disease-modifying therapy (HU, CT, or SCT),
whichever occurred first. Only episodes of pain or ACS that occurred before the
start of any disease-modifying therapy (HU, CT or SCT) were included, because
such treatments are expected to alter the natural frequency of these events. The
use of a disease-modifying therapy was also studied as a surrogate measure of
disease severity.
For purposes of this study, we defined CT to be a program of regularly scheduled
red blood cell transfusions of at least 6 months’ duration given for the prevention
of complications of SCD. In our center, CT is used to prevent recurrent stroke
and, in select patients, to prevent frequent pain or recurrent ACS. At the time of
this analysis, we had not commonly used CT for primary stroke prevention. We
defined HU use as any administration of HU without regard to duration of
treatment or a subject’s adherence. HU is prescribed on an individual basis for
patients who have frequent pain or recurrent ACS, or when CT is not preferred
by the patient and family. To date, we have performed SCT only for prevention of
recurrent stroke.
Statistical Analysis
Bivariate Analysis. We compared the frequencies of the late categorical
outcomes (death, stroke, and use of disease-modifying therapy) between the
early predictor-positive and predictor-negative groups by two-sided Fisher’s exact
tests. For these bivariate analyses (predictor-outcome groupings), we studied the
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occurrence of early vaso-occlusive complications as binary variables (namely,
the occurrence or not of at least one complication). The predictive utility of
multiple early hospitalizations was tested in the multivariate analysis (see below).
For statistically significant associations, we calculated odds ratios (OR) with 95%
confidence intervals (95% CI).
We assessed differences in the occurrence of late pain and ACS between the
early predictor-positive and predictor-negative groups using means, mean
differences, and two-sided t-tests. To control for subjects’ different lengths of
follow-up, we classified each episode of pain and ACS by the subject’s age at the
time of its occurrence. Episodes were then categorized into non-overlapping 2-
year intervals defined by age of occurrence (3-4.99, 5-6.99, 7-8.99, 9-10.99, 11-
12.99, 13-14.99, 15-16.99, and 17-18.99 years of age). To additionally provide a
meaningful number of events for analysis these intervals were combined
cumulatively (3-6.99, 3-8.99, 3-10.99, 3-12.99, 3-14.99, 3-16.99, and 3-18.99
years of age), and the mean number of episodes of pain or ACS was calculated
in each interval. The pain and ACS episodes experienced by an individual were
included in one or more of these cumulative intervals only if he or she was alive
and evaluable in that interval.
For the bivariate analyses, P-values < 0.01 were considered statistically
significant to partially control for multiple comparisons.
Multivariate Analysis. We used binary logistic regression with backward model
building to predict late outcomes from early vaso-occlusive events. Here we
studied the number of early vaso-occlusive complications as a continuous
variable (to assess the contributions of multiple early events), unlike in bivariate
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analysis, wherein we considered only their occurrence or not. We included these
variables as predictors: early pain (excluding dactylitis), early dactylitis, early
ACS, sex, and genotype (SS or Sβ0). Logistic regression models were
constructed for the following outcomes: (1) death or stroke; (2) occurrence of late
painful episodes; (3) occurrence of late ACS; and (4) the composite occurrence
of late pain and ACS.
For each subject, we calculated rates of late pain and ACS that included all
events in the interval between the third birthday and the last clinical encounter, or
the start date of a disease-modifying therapy (HU, CT, or SCT), whichever
occurred first. Because the rates of late pain and ACS were not normally
distributed, and could not be normalized by transformation, multiple linear
regression was not tenable. Therefore, the rates of late pain and ACS were made
dichotomous for binary logistic regression in two different ways: (1) dichotomous
at the median rate for the whole sample (rate ≤ median vs. rate > median), and
(2) dichotomous at 1 episode/year (rate < 1 episode/year vs. ≥ 1 episode/year).
The cut-off of 1 episode/year was chosen in addition to the median because
some clinicians consider it to be a clinically meaningful threshold that denotes
disease severity. We calculated ORs and a 95% CIs for statistically significant
predictors in the model. We did not attempt to predict the late use of HU, CT, or
SCT, because bivariate analysis showed that CT and SCT were not associated
with early vaso-occlusive complications, and we believed that HU use was
largely a surrogate marker for late pain and ACS.
All data were analyzed using SPSS 13.0 statistical software (SPSS Inc.,
Chicago, IL, USA). Figures were generated using GraphPad Prism 4.0c
(GraphPad Software, San Diego, CA, USA).
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RESULTS
There were 264 subjects (55% male, 97% SS) in the analysis. The mean age at
first visit was 4.1 months [standard deviation (SD) 2.3 months], and the mean
length of follow-up was 12.1 years (SD 4.3 years). Twenty of 264 (7.6%) were
classified as lost to follow-up.
We found no statistically significant differences between males and females or
between SS and Sβ0 genotypes for any of the early or late events (data not
shown). All early and late events are reported in Table 1. Two subjects died of
pneumococcal sepsis (5 and 6 years of age), and one subject each died of acute
chest syndrome (5 years), complications of multiple strokes (7 years), and Down
syndrome with multiple congenital anomalies (5 years).
Bivariate Analysis
Associations of Early Events with Death and Stroke. We found that
hospitalization for pain, dactylitis, or ACS in the first three years of life did not
predict later death or clinically overt stroke (Table 2). Notably, none of the
subjects who had dactylitis later died or had a stroke. This superficially
“protective” effect of dactylitis was not statistically significant, so a true protective
effect should not be inferred. Because death and stroke were infrequent
outcomes, we also studied these two events as a single, composite outcome and
found, similarly, no associations with any of the early vaso-occlusive
complications.
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Associations of Early Events with Use of HU, CT, or SCT. We found that
early vaso-occlusive complications predicted only the later prescription of HU
(Table 2). The occurrence of early painful episodes gave an OR for later HU use
of 3.53 (95% CI 1.63, 7.64). Early ACS gave an OR for HU use of 5.69 (95% CI
2.55, 12.69). However, children who were hospitalized only for early dactylitis,
and not for pain or ACS, were not more likely to be treated with HU (P > 0.999;
Table 2). Early vaso-occlusive complications were not associated with later
initiation of CT. The single subject who underwent SCT to prevent recurrent
stroke was not hospitalized for pain, dactylitis, or ACS in the first three years of
life.
Associations of Early Events with Late Pain (Figure 1). We found that
subjects who were hospitalized for early painful episodes, compared to those
who were not, had a small increase in the mean number of late painful episodes
through approximately 11 years of age, but this effect was not seen in longer
periods of follow-up. Similarly, subjects who were hospitalized for early ACS had
a slightly higher mean number of late painful episodes through approximately 11
years of age, but not beyond. Dactylitis was not associated with more frequent
late pain considering periods of follow-up that were less than 18 years. However,
for the few subjects who had follow-up of 18 years or greater (N = 38), dactylitis
was associated with a statistically significantly increased number of late painful
episodes over the entire period of follow-up (Figure 1).
Associations of Early Events with Late ACS (Figure 2). There were no
associations between early pain or dactylitis and the mean number of late
episodes of ACS. However, children who were hospitalized for early ACS had an
increased mean number of late ACS episodes throughout all childhood. The
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mean difference was as high as 3.7 episodes of late ACS when comparing early
ACS-positive and ACS-negative subjects (Figure 2).
Multivariate Analysis
Death and Stroke. Neither alone nor in any combination did early pain, early
dactylitis, early ACS, sex, and genotype predict death and stroke. This was
consistent with the bivariate analyses.
Late Pain. Early VOC predicted the rate of late hospitalizations for pain if the cut-
off was set at the median rate for all subjects (≤0.071 vs. >0.071 episodes of
pain/year), but only 6% of the variability in late pain was explained by this model
(Table 3). If this cut-off was set instead at 1 episode/year, then early VOC was
not predictive, but early ACS was; however, this model explained only 5% of the
variability in late pain (Table 3). Early dactylitis, sex, and genotype were not
predictive of the occurrence of late pain. Thus, these models poorly predicted
late pain.
Late ACS. The only statistically significant predictor of the occurrence of late
ACS was early ACS itself, whether considering the cut-off rate at the median for
all subjects (≤0.1125 vs. >0.1125 episodes of ACS/year) or 1 episode/year
(Table 3). These models explained 15% and 24%, respectively, of the variability
in late ACS (Table 3). Early pain, early dactylitis, sex, and genotype did not
predict the occurrence of late ACS.
Late Pain and ACS. The only statistically significant predictor of the occurrence
of late pain and ACS (the composite outcome) was early ACS, whether
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considering the cut-off rate at the median (≤0.25 vs. >0.25 episodes of pain and
ACS/year) or 1 episode per year (Table 3). These models explained 15% and
12%, respectively, of the variability in late pain and ACS (Table 3). Early pain,
early dactylitis, sex, and genotype did not predict the occurrence of late pain and
ACS.
DISCUSSION
It is difficult to predict severe SCD during childhood, at least in part, because it is
difficult to define severe disease.1 Two objective indicators of disease severity
are death and stroke.3,11 Fortunately, both are becoming rare in children, given
the diminishing mortality from invasive bacterial infection and splenic
sequestration, as well as the prevention of first stroke using TCD to direct the
initiation of chronic red blood cell transfusions. Beyond these two objective
outcomes, investigators and clinicians have relied upon the enumeration of
hospitalizations for vaso-occlusive complications as an index of disease severity,
however imperfect. For example, the inclusion criteria for therapeutic clinical
trials typically require frequent painful episodes or recurrent ACS,12,13 but the
definitions of these events and the particular criteria used to denote severity are
not uniform. In the absence of good alternatives, we also studied these usual
measures of disease severity here, but we did not arbitrarily define a rate of pain
or ACS that was “severe”.
We showed that hospitalizations for vaso-occlusive complications during the first
three years of life did not predict the most objective markers of severe SCD:
death and stroke. The low incidence of death in the Dallas Newborn Cohort
reflects universal newborn screening and the uniform use of prophylactic
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penicillin. The CSSCD showed no association between overall pain rate and
stroke,11 and we found no increased risk of stroke from pain events that occur in
very early childhood. The incidence of stroke in the Cohort at the time of this
analysis, however, does not reflect the impact of primary stroke prevention,
because our center only recently instituted a TCD screening program.
Fortunately, death and stroke are becoming rare in children with SCD, so the
sickle cell community is now challenged to use other measures of severe
disease.
We studied the use of a disease-modifying therapy as a proxy for severe disease
and found that early vaso-occlusive complications predicted neither the later use
of CT nor SCT. This is not surprising, because stroke is the most common
indication for both CT and SCT. As such, neither stroke nor its proxies, CT and
SCT, was predicted by early vaso-occlusive complications. On the contrary, early
vaso-occlusive complications were associated with more frequent later use of
HU. Although this association is neither surprising nor wholly unexpected, it
should also be interpreted with caution because the decision to prescribe HU to
older children was likely biased by the knowledge that they had experienced
early complications. The imputation of disease-modifying therapy as a surrogate
marker of disease severity is also influenced by the varying prescribing practices
of physicians. Therefore, we also studied the frequency of late pain and ACS as
more direct, less biased indicators of disease severity.
We found that hospitalizations for pain or ACS in the first three years of life
predicted only a small and temporary increase in later painful events. Moreover,
the multivariate models could explain only a very small fraction of the variability in
late pain. It is unclear if such a modest increase in pain is clinically significant.
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Neither early dactylitis nor pain was associated with late ACS, but subjects who
had early ACS were more likely to have recurrent ACS throughout childhood.
Although factors other than early ACS, which are unknown, unmeasured, or both,
accounted for much of the variability in late ACS (Table 3), we infer a distinct
susceptibility to recurrent ACS. Perhaps ACS-related pulmonary injury
predisposes to subsequent ACS. An early study by Powars et al. suggested that
recurrent ACS caused chronic sickle cell lung disease.14 However, ACS in young
children tends to be mild,15 and recent studies indicate that neither pulmonary
hypertension16 nor steady-state oxyhemoglobin desaturation17 is associated with
prior ACS. Another interpretation is that the observed effect is due to asthma and
not ACS itself, but it is difficult to separate these two disease processes given the
definition of ACS as an acute pulmonary illness in an individual with SCD and
that bronchospasm and hypoventilation can precipitate ACS. So, asthma could
be the cause or consequence of ACS, or the two could share a common
pathophysiology. Indeed, Boyd and colleagues reported an association between
asthma and ACS,18 and Morris et al. found similar alterations of arginine
metabolism in both asthma and ACS.19,20
In the CSSCD infant cohort, the occurrence of dactylitis in the first year of life
conferred a relative risk of 2.6 for severe disease.9 Although our investigation
was not designed to refute or validate this particular CSSCD finding, which
included both inpatient and outpatient episodes of dactylitis, we found in contrast
that hospitalization for dactylitis in the first three years of life had limited
prognostic utility in the Dallas Newborn Cohort. Hospitalization for dactylitis did
not predict death, overt stroke, the use of a disease-modifying therapy, or later
ACS. Early dactylitis was also not associated with late pain, except in one
correlation with the 38 subjects who had 18 years or more of follow-up. This is an
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interesting observation that differs from the predictive pattern of early pain and
ACS for later pain events (Figure 1). Perhaps early dactylitis is associated with
an increase in late pain over a long period of follow-up, but the size of this sub-
group is small and the variability of this particular estimate of mean difference is
too high to justify strong inferences.
This retrospective analysis has a number of limitations. First, we studied only
hospitalizations for pain, dactylitis, and ACS. Many episodes of pain and
dactylitis are managed only at home and not in a hospital or an outpatient facility,
and we did not systematically record these outpatient events. Although many
factors unrelated to SCD, such as family situation and coping skills, determine
whether a patient is admitted to a hospital or not, generally the more severe
episodes are managed by hospitalization. Thus, we have studied the
associations among the relatively more severe of the early and late
manifestations of SCD. Second, the missing data of patients who were lost to
follow-up and censored at their last clinical encounter may have biased the
outcomes in either direction; however, there were not many lost subjects. Third,
there are numerous clinical, laboratory, and psychosocial factors that could
influence outcomes in SCD that we did not consider here. We could not
reasonably analyze so many predictors in a cohort of this size, however large.
Instead we chose a priori a small number of predictors and outcomes to test a
simple clinical question, and we realize that there may be confounding variables
that we have neither measured nor controlled for. Fourth, it is possible that
therapeutic improvements over the period of observation in this study could have
decreased the predictive nature of the early events, although such an effect
would probably be small given the mean follow-up of 12 years. Fifth, the use of
disease-modifying interventions in older individuals, which would decrease the
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frequency of late pain events, might partly account for the lack of association
between early events and late events after age 11 years. The overall rate of pain
in the study population increased after age 11 years and remained higher until 17
years (data not shown), so such confounding might be modest, but it cannot be
dismissed. Moreover, such a censoring effect is not apparent in dactylitis data.
Lastly, even though we nominally controlled for multiple comparisons, some of
the statistically significant associations we found may still have been type I
errors.
In summary, we have shown that ACS during the first three years of life predicts
recurrent ACS throughout childhood. A potential approach to reduce this risk may
be to screen for and aggressively manage any asthma-like disease in children
who have early ACS, and this strategy should be the focus of further research.
The prognostic significance of other early vaso-occlusive complications is quite
limited. Notably, none of the early events predicted the most objective
manifestations of severe SCD: death and stroke. Although a multitude of
predictors of outcome have been studied,1 we still lack a useful prognostic
framework for infants and young children with SCD. Until we are better at
prognostication, we should not endorse the use of a disease-modifying therapy in
very young children based solely on the occurrence of a few episodes of early
pain or dactylitis. Children who experience ACS in the first three years of life,
however, might be candidates for early, higher risk interventions to mitigate or
cure SCD.
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REFERENCES
1. Quinn CT, Miller ST. Risk factors and prediction of outcomes in children
and adolescents who have sickle cell anemia. Hematol Oncol Clin North Am.
2004;18:1339-1354.
2. 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.
3. Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease.
Rates and risk factors. N Engl J Med. 1991;325:11-16.
4. Serjeant GR, Richards R, Barbor PR, Milner PF. Relatively benign sickle-
cell anaemia in 60 patients aged over 30 in the West Indies. Br Med J.
1968;3:86-91.
5. Steinberg MH, Dreiling BJ, Morrison FS, Necheles TF. Mild sickle cell
disease. Clinical and laboratory studies. Jama. 1973;224:317-321.
6. Steinberg MH, Rodgers GP. Pathophysiology of sickle cell disease: role of
cellular and genetic modifiers. Semin Hematol. 2001;38:299-306.
7. Weatherall DJ. Phenotype-genotype relationships in monogenic disease:
lessons from the thalassaemias. Nat Rev Genet. 2001;2:245-255.
8. Health supervision for children with sickle cell disease. Pediatrics.
2002;109:526-535.
9. Miller ST, Sleeper LA, Pegelow CH, et al. Prediction of adverse outcomes
in children with sickle cell disease. N Engl J Med. 2000;342:83-89.
For personal use only.on September 16, 2016. by guest www.bloodjournal.orgFrom
QUINN et al. Significance of Early Vaso-Occlusive Complications
19
10. Quinn CT, Rogers ZR, Buchanan GR. Survival of children with sickle cell
disease. Blood. 2004;103:4023-4027.
11. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular
accidents in sickle cell disease: rates and risk factors. Blood. 1998;91:288-294.
12. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the
frequency of painful crises in sickle cell anemia. Investigators of the Multicenter
Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med. 1995;332:1317-1322.
13. Walters MC, Patience M, Leisenring W, et al. Bone marrow transplantation
for sickle cell disease. N Engl J Med. 1996;335:369-376.
14. Powars D, Weidman JA, Odom-Maryon T, Niland JC, Johnson C. Sickle
cell chronic lung disease: prior morbidity and the risk of pulmonary failure.
Medicine. 1988;67:66-76.
15. Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the
acute chest syndrome in sickle cell disease. National Acute Chest Syndrome
Study Group. N Engl J Med. 2000;342:1855-1865.
16. Gladwin MT, Sachdev V, Jison ML, et al. Pulmonary hypertension as a
risk factor for death in patients with sickle cell disease. N Engl J Med.
2004;350:886-895.
17. Quinn CT, Ahmad N. Clinical correlates of steady-state oxyhaemoglobin
desaturation in children who have sickle cell disease. Br J Haematol.
2005;131:129-134.
18. Boyd JH, Moinuddin A, Strunk RC, DeBaun MR. Asthma and acute chest
in sickle-cell disease. Pediatr Pulmonol. 2004;38:229-232.
For personal use only.on September 16, 2016. by guest www.bloodjournal.orgFrom
QUINN et al. Significance of Early Vaso-Occlusive Complications
20
19. Morris CR, Kuypers FA, Larkin S, Vichinsky EP, Styles LA. Patterns of
arginine and nitric oxide in patients with sickle cell disease with vaso-occlusive
crisis and acute chest syndrome. J Pediatr Hematol Oncol. 2000;22:515-520.
20. Morris CR, Poljakovic M, Lavrisha L, Machado L, Kuypers FA, Morris SM,
Jr. Decreased arginine bioavailability and increased serum arginase activity in
asthma. Am J Respir Crit Care Med. 2004;170:148-153.
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FIGURE LEGENDS
Figure 1. Associations between Early Predictors and Late Episodes of Pain.
Depicted here are the mean differences in the number of late painful episodes for
groups defined by the occurrence or not of each of the three early predictors
(whiskers are standard errors). Mean difference = (mean number of painful
episodes in predictor positive group) – (mean number of painful episodes in
predictor negative group). The mean differences are shown for cumulative,
overlapping intervals of follow-up beginning with the third birthday. (**P < 0.01;
***P < 0.001)
Figure 2. Associations between Early Predictors and Late Episodes of ACS.
Depicted here are the mean differences in the number of late episodes of ACS
for groups defined by the occurrence or not of each of the three early predictors
(whiskers are standard errors). Mean difference = (mean number of ACS
episodes in predictor positive group) – (mean number of ACS episodes in
predictor negative group). The mean differences are shown for cumulative,
overlapping intervals of follow-up beginning with the third birthday. (*P < 0.05; **P
< 0.01; ***P < 0.001)
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Table 1. Early Predictors and Late Outcomes.
Children who Experienced Events Early and Late Events Number of
Events Number Percenta
Early predictors
Painful eventsb 89 54 20.5
Dactylitis 18 16 6.1
ACS 151 86 32.6
Late outcomes
Death of any cause 5 5 1.9
First clinically overt stroke 30 30 11.4
Use of HU, CT or SCT 78 66 25
Painful events 642 130c 49.2c
Acute chest syndrome 410 150c 56.8c
aTotal N = 264 subjects bExcluding dactylitis cSubjects who experienced one or more events
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23
Table 2. Associations between Early Predictors and Late Death, Stroke, or the
Use of HU, CT, or SCT.
Occurrence of Early Predictors (Yes or No)
Frequency of Painful Episode Dactylitis ACS
Late Outcomes Yes No P Yes No P Yes No P
Death (%) 1.9 1.9 >0.999 0 2.2 >0.999 2.4 1.7 0.666
Stroke (%) 13.2 10.2 0.619 0 11.6 0.231 14.1 9.8 0.303
Death or Stroke (%) 13.2 12.1 0.817 0 13.2 0.233 15.3 11.6 0.43
HU (%) 26.4 9.2 0.002 12.5 12.4 >0.999 25.9 5.8 <0.001
CT (%) 17 14.1 0.663 6.3 15.3 0.48 20 12.7 0.141
SCT (%) 0 0.5 >0.999 0 0.4 >0.999 0 0.6 >0.999
The percentage of subjects who experienced each outcome is shown based on the
occurrence or not of each early predictor. P-values are calculated for each comparison
of percentages (yes vs. no) using Fisher’s exact test.
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24
Table 3. Summary of Predictive Variables in the Multivariate Models.
Late Rates Dichotomous at Median Number of Events/Year
Late Rates Dichotomous at 1 Event/Year Early Predictive Variables
P OR 95% CI R2
P OR 95% CI R2
For outcome: Late Pain Early pain (non-dactylitis) 0.002 1.93 1.26, 2.95 0.060 — — —
Early ACS — — — 0.009 1.57 1.12, 2.21 0.053
For outcome: Late ACS
Early ACS <0.001 2.23 1.52, 3.29 0.149 <0.001 2.51 1.67, 3.86 0.236
For outcome: Late Pain and ACS
Early ACS <0.001 1.92 1.36, 2.70 0.152 <0.001 1.93 1.42, 2.62 0.123
Odds ratios (ORs) are calculated by binary logistic regression analysis, which adjusts
for sex, genotype, early non-dactylitis pain, early dactylitis, and early ACS episodes as
appropriate. ORs correspond to a single unit increase in the predictive variable (an
episode of ACS or pain, where appropriate). Nagelkerke R2 values are reported as
coefficients of determination and indicate the proportion of variability in the outcomes
explained by the models.
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doi:10.1182/blood-2006-02-005082Prepublished online August 29, 2006;
BuchananCharles T Quinn, Elizabeth P Shull, Naveed Ahmad, Nancy J Lee, Zora R Rogers and George R with sickle cell anemiaPrognostic significance of early vaso-occlusive complications in children
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