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Clinical Events in the First Decade in a Cohort of Infants With
Sickle Cell Disease
By Frances M. Gill, Lynn A. Sleeper, Steven J. Weiner, Audrey K. Brown, Rita Bellevue, Ranjeet Grover,
Charles H. Pegelow, and Elliott Vichinsky for The Cooperative Study of Sickle Cell Disease
Within the Cooperative Study ofSickleCellDisease,694
infants with confirmed sickle cell disease were enrolled at
less than 6 months of age.
Information about the nature and
frequency of complications
was collected prospectively over
a IO-year period. Painful crises and acute chest syndrome
were the most common sickle cell-related events
in homozygous sickle cell anemia (SS), hemoglobin SC disease (SC),
and Sa thalassemia patients [overall incidence in SS patients of 32.4 and 24.5 cases per 100 person-years, respectively). Bacteremia occurred most frequently in SS children
under 4 years of age andin SC patients less than 2 years of
age. The mortality rate was low in this cohort compared
with that found in previous reports.
Twenty children, all with
Hb SS. died 11.1 deathsper 100 person-yearsamong SS
patients). Infection, most commonly with Streptococcus
pneumoffiaeand Hemophilus influenzae,caused 11 deaths.
Two children died of splenic sequestration, 1 of cerebrovascular accident, and 6of unclear causes. Two patients underwent cholecystectomies, and 17 underwent splenectomies
after one or more splenic sequestration crises. The experienceof this cohort should reflect closely the true clinical
course ofthose childrenwith Hb SS and Hb SC disease who
are observed in sickle cell centersin the United States.
0 1995 by The American Society of Hematology.
T
and 53% (365) were male. The majority of infants (77% during
the first 3 years) were identified in the newborn hemoglobinopathy
screening programs conducted atthe centers. Other infants were
referred to the centers after being diagnosed as having sickle cell
disease.
The mean entry age was3.0 t 1.4 months(mean i 1 standard
deviation), and the mean period of follow-up was 4.2 2 2.6 years.
Twenty-five percent ofthe sample was observed for more than 6
years. Over theIO-year period, 20 patients (2.9%) diedand 161
(23.2%) were lost to follow-up (20.1% of SS patients, 27.2% of SC
patients, 37.5% of Sp', and 2 1.4% ofSp" patients). The mean length
of study participation for the infants lost to the study was 3.0 f 2. l
years, compared with 4.7 2 2.6 years for those who were retained
in the study and who did not die. Of those lost to follow-up, 27%
participated in the study for 4 or more years. Table 1 provides details
of the composition and follow-up of the cohort. There were less
than 100 person-years of observation for SS patients morethan 6
years of age and SC patients more than 5 years of age. Data on the
experience of children at older ages will accrue as this cohort ages.
HE COOPERATIVE STUDY of Sickle Cell Disease
(CSSCD) is a multicenter, longitudinal study that began patient enrollment in 1978. Within this study a subset
of children was enrolled before 6 months of age at the time
of a routine visit to a participating center. Information from
this infant cohort is of particular value because data on all
significant events have been prospectively collected. The
experience of children over a 10-year period is reported here.
A report of preliminary data on some events was presented at
the National Institutes of Health (NIH)-sponsored Consensus
Workshop for Hemoglobinopathy Screening in the Newborn.'
MATERIALS AND METHODS
Patients
The designthe
of
CSSCD has been described
Nineteen clinical centers entered 703 infants less than 6 months of age
into the study between October 1978 and October 1988. The hemoglobin diagnosis was not confirmed in 9 infants; 694 infants with
confirmed hemoglobin genotype are included in this analysis. Sixtytwo percent of the infants had homozygous sickle cell anemia (SS),
32% hemoglobin SC disease (SC), 5% Sp' thalassemia (Sp'), and
2% SO" thalassemia (Sp'). Forty-seven percent (329) were female
From The Division of General Pediatrics, Department of Pediatrics, The University of Pennsylvania School of Medicine, Philadelphia, PA;theNewEngland
Research Institutes, Watertown, MA;
the Department of Pediatrics, State University of New York Health
Science Center at Brooklyn, NY; Interfaith Medical Center, Comprehensive Sickle Cell Program, Brooklyn, NY; St Luke Hospital Sickle
Cell Program, New York, NY; the Division of Pediatric Hematology,
University of Miami, Miami, FL; and Oakland Children's Hospital,
Oakland, CA.
Submitted December 30, 1994; accepted February 23, 1995.
Supported by the Division of Blood Diseases and Resources of
the National Heart, Lung, and Blood Institute.
Address reprint requests to Frances M. Gill, MD, The Children's
Hospital of Philadelphia, 34th and Civic Center Blvd, Philadelphia,
P A 19104.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
0 1995 by The American Society of Hematology.
0006-4971/95/8602-0003$3.00/0
776
Laboratory Diagnosis
The Centers for Disease Control (CDC) determined the hemoglobin genotype by cellulose acetate and citrate agar electrophoreses
and by quantitation ofthe fetal hemoglobin and hemoglobin A,
have a CDClevels. There were 42 infants (6.1%) whodidnot
confirmed diagnosis; the hemoglobin diagnosis of the participating
center's laboratory was used instead. Complete blood counts were
performed at the local center. a-Globin gene mapping to determine
the presence of 01 thalassemia was performed on samples from 3 10
of the 427SS infants (73%) by Dr Stephen H. Embury at the University of California at San Francisco.?,'
Data Collection
Standardized forms wereused to record data collected during
visits to the centers for scheduled visits and for acute events. Visits
were scheduled for health maintenance in these young children at
2, 4, 6 , 9, 12, 15. 18, 21, and24 months andyearly thereafter.
Patients included in this study received all their care, including that
for acute events. at the participating centers. An acute event form
was completed each time a patient came to the clinic or emergency
room or was hospitalized for an event related to sickle cell disease.
No attempt was made to set standard protocols for treatment of
patients enrolled in the study. Specifically, there were no set recommendations for use of red blood cell transfusions, use of daily penicillin for prevention of infection, or age at administration of pneumococcal vaccine. However, in 1986 use of penicillin V administered
in two daily doses for prophylaxis became standard therapy in all
study centers. Polyvalent pneumococcal vaccine was administered
Blood, VOI 86, NO 2 (July 15), 1995:pp 776-783
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777
THE FIRST DECADE IN SICKLE CELL DISEASE
Table 1. ComDosition of the Infant Cohort
Hemoglobin
Genotype
Patients
~~~
1.781.4
ss
sc
62
Sg+ thalassemia
S@' thalassemia
Total
96
Person-Years of
Observation*
~
427
221
32
14
694
32
5
2
100
951.2
117.6
58.2
2,908.3
* Excludes 76.3 person-years of follow-up time accrued after the
institution of chronic transfusion programs. For SS and Sg'thalassemia patients, complete follow-up time was 1,851.7 person-years
and 64.2 person-years, respectively.
excluded because of chronic transfusion programs. Group comparisons of incidence rates were conducted using exact binomial and
the normal approximation to binomial hypothesis testing methods.
Ninety-five percent confidence intervals (CI) were constructed using
the normal approximation to the binomial distribution.
Kaplan-Meier event-free survival curves were estimated and compared using the logrank test6 Time to event was measured by age
rather than time on study, because follow-up began close to the time
of birth.
Descriptive statistics are presented as percentages and means 2
1 standard deviation. All hypothesis tests and confidence intervals
are two-sided. A P value of .05 or less was considered a significant
result.
RESULTS
to the study children, but each center determined the age of immunization. This age varied from 6 months at initial vaccination with
revaccination at 2 years to initial vaccination at 2 years of age.
Hemophilus influenzae type B vaccine became available in 1985 and
was recommended for use at 18 months in sickle cell patients. The
improved, conjugated vaccines used in infants were not available
until 1990, after the period covered in this report.
Dejinition of Events
Sickle cell-related events were defined in a manual of operation
used in each center. Only events that brought the child to the center
for medical care were recorded. Standard treatment protocols or
transfusion criteria were not set for the events. The event definitions
were as follows. A painful event was defined as pain in the extremities, back, abdomen, chest, or head for which no other explanation
(eg, osteomyelitis or appendicitis) could be found. Meningitis was
defined as abnormal cerebrospinal fluid (CSF) findings and culture
of CSF. Acute anemic episode was defined as either an acute splenic
sequestration defined as a decrease of the hemoglobin or hematocrit
level of at least 20% from baseline accompanied by an increase in
palpated spleen size of at least 2 cm from baseline or as another
acute anemic event defined by an acute reduction of the hemoglobin
or hematocrit level of at least 30%from baseline and not caused by
non-sickle cell problems (eg, blood loss, cancer, etc). Itwasnot
possible to clearly separate other anemic events into aplastic episodes
or hyperhemolytic episodes, so these were grouped as other anemic
events for analysis. Clinical centers classified only six events as
being hyperhemolytic. Acute chest syndrome was defined as the new
appearance of an infiltrate on chest radiograph or, in presence of
pulmonary symptoms and negative chest radiograph, abnormalities
on an isotopic scan of the lungs. A skeletavjoint event was defined
as acute pain involving one or more bones that lasted at least 7 days;
osteomyelitis with identification of an etiological agent by culture;
or nontraumatic swelling of one or more joints with pain or effusion.
A patient entering with pain in his extremities would be recorded
as a painful event, but if the pain lasted in the bone(s) for 7 days,
a skeletalfjoint event form would be completed. Hand-foot syndrome
was defined as pain and tenderness, with or without swelling, in the
hands and/or feet of a child less than 10 years old. These events
were reported on a hand-foot form rather thanon a skeletayjoint
event form. A cerebrovascular accident (CVA) was defined as an
acute neurologic syndrome secondary to the occlusion of an artery
or to hemorrhage with resultant neurologic symptoms and signs.
Statistical Analysis
Incidence rates are presented as the number of cases per 100
person-years. To obtain incidence estimates that reflect the natural
history of sickle cell disease, rates (for all events except transfusion)
were based on events and follow-up time that preceded the institution
of a chronic transfusion program; 2.6% of all follow-up time was
Incidence of Events
The incidence rates by age of the most common problems
in Hb SS and SC patients are given in Table 2. All events
with a positive blood culture result are included in the bacteremia category, even if there was an associated event such
as meningitis. There were too few patients with S@thalassemia to define accurate incidence rates.
There was no difference by gender in the incidence of
acute anemic events, bacteremia, hand-foot syndrome, CVA,
right-upper quadrant syndrome, receipt of transfusion, or
death. Hb SS male children had a significantly higher incidence of acute chest syndrome (29.l v 20.1, P = .Owl)than
did female children. Hb SS female patients had a significantly higher incidence of painful crises than did male patients (35.7 v 28.9, P = .0122). The reasons for these differences are unknown. All results given below are for combined
genders.
All deaths occurred in Hb SS patients with an overall
incidence of 1.1 per 100 person-years (95% CI, 0.6 to 1.6).
Time to First Event
The data were used to determine the time until the first
episode of selected complications. The time was significantly
shorter in Hb SS compared with that in SC patients ( P S
.01) for painful crisis, acute chest syndrome, all acute anemic
events, splenic sequestration, hand-foot syndrome, bacteremia, transfusion, and CVA. Figure 1 shows the estimated
percentage of patients experiencing a first event by a specified age for six common events.
The risk of painful crisis and acute chest syndrome begins
in the first year of life and increases steadily (Fig l). Half
of all SS and SC patients experience a painful crisis by 4.9
years and 7.1 years of age, respectively. The acute chest
syndrome is experienced byhalfof all SS patients by 5.8
years of age. Hand-foot syndrome is uncommon in SC patients, whereas one quarter of SS patients seek medical care
for this event by 2.5 years of age. Acute anemic events are
also uncommon in SC patients, but 10% of SS patients have
had a splenic sequestration event by 3 years of age.
Event Recurrence
The risk of event recurrence was examined for the following events: acute anemia, painful crisis, acute chest, handfoot syndrome, and bacteremia. There were significant differences by hemoglobin genotype for recurrence of the acute
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GILL ET AL
778
Table 2. Incidence per 100 Person-Years by Age
Anemia
Age
<6 mo
2.0
6-12mo
18.2
1 Yr26.8
10.6
2 Yr26.3
10.4
3 Yr34.2
1.5
4 yr25.5
6.2
5.3
Genotype
Painful Event
Bacteremia
Acute Chest
Splenic
Other
Hand-Foot
CVA
ss
sc
2.9
0.0
9.5
3.8
24.0
8.5
38.3
15.3
42.4
1.528.5
49.6
23.3
40.82.0
33.6
39.2
29.1
41.6
40.3
37.9
23.0
l .9
6.8
3.5
16.4
1 .o
0.0
5.5
0.0
2.9
0.0
5.0
0.0
14.6
0.0
31.3
1 .o
0.0
0.0
3.2
0.0
1.2
ss
sc 7.7
ss6.5
sc
5.8
ss
8.7
1.2
sc
ss4.7
sc
ss
2.0
sc
5 yr
ss
sc
628.9
1.8
7 Yr20.8
ss
4.1
1.8sc
ss
1.5
sc
8-10yr
ss
sc
0.0
9.9
0.0
1.5
0.0
13.1
0.0
0.0
1.4
1.30.0
9.7
22.5
5.2
2.9
1 .o
0.0
0.0
0.0
chest syndrome ( P < .01) and bacteremia ( P < .001). One
quarter of S S patients experiencing the acute chest syndrome
had a recurrent event within 6 to 9 months, whereas one
quarter of SC children had a recurrent event within 3 years.
Bacteremia recurred in 20 percent of S S children within 18
months, but recurrence was rare among the SC patients.
Painful crisis recurred within 6 months in 32% of S S patients
and 19% of SC patients. Hand-foot syndrome recurred within
6 months in 25% of S S and in 12% of SC children.
Effect of cv Thalassemia
a-Globin gene typing of 310 S S children showed that 10
(3.2%)had 2, 90 (29.0%) had 3, 207 (66.8%) had 4,and 3
(1.0%) had 5 cv genes. Analysis of the incidence of clinical
events was performed for the 100 patients with cv thalassemia
(2 or 3 genes) and for the 210 who had 4 or 5 cv genes (Table
3 ) . Children with cv thalassemia had a significantly higher
incidence of painful events and a significantly lower incidence of acute chest syndrome and of acute anemic events
other than splenic sequestrations.
Specific Events
Bacteremia. Bacteremia, defined as an acute event with
positive blood culture results, occurred as an isolated event
or in association with other complications such as acute
chest syndrome, meningitis, osteomyelitis, and urinary tract
infection. The responsible organism and associated events
are detailed in Table 4. In Hb S S patients, the mortality rate
was 14.5%in the 62 bacteremic infections with Streprococcus pneumoniae and 20.0% in the 10 bacteremic infections
with H injluenzae. There were no deaths from bacteremia in
the Hb SC patients or in SP thalassemia patients.
Four bacteremic events occurred in 2 of the 32 Sp+ thalassemia patients. One patient had two infections 2 weeks apart
with P-hemolytic streptococcus. The other patient had an
5.8
0.0
15.2
3.3
0.0
0.0
0.0
0.0
0.0
0.0
0.0
8.3
0.0
3.0
0.0
1.9
0.0
2.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
1.5
0.7
2.1
1.5
0.0
0.0
acute chest syndrome caused by S pneumoniae and 2 years
later sepsis with p hemolytic streptococcus. No episodes of
bacteremia occurred in the 14 SPo thalassemia patients.
Seventeen patients had bacteremia more
than
once.
Twelve S S , 1 SC, and 2 SP+ patients had two episodes, and
2 S S patients had three. None of these patients died.
Meningitis. There were 15 episodes of meningitis in Hb
S S patients. Ten cases were caused by S pneumoniae. In
addition to the 8 patients with positive blood culture results
detailed above, 1 patient had a positive cerebrospinal fluid
culture result but a negative blood culture result. In another
patient who had received ampicillin before the diagnosis of
meningitis, the CSF findings were compatible with bacterial
meningitis, and the urine CIE was positive for Spneumoniae.
One case was caused by H injluenzae, and 4 were presumed
to be viral because no organism was isolated.
Of the 8 cases of meningitis in Hb SC patients, 1 was
caused by H injluenzae and 7 were presumed to be viral
events. The reason for the higher incidence of viral meningitis in the SC patients is unknown. No cases of meningitis
occurred in the S@ thalassemia patients.
The incidence of bacteremia with S pneumoniae and H
injluenzae and resulting mortality rate in Hb S S patients by
calendar year is shown in Fig 2. Variation in the incidence
is seen from year to year, as has been previously described.'
Acute anemic events.
In the S S cohort, 76 children had
127 acute anemic episodes. Forty-three patients had 61 acute
splenic sequestration events, and 16 of these patients underwent splenectomy. Patients requiring splenectomy had a median age of 1.6 years (range, 0.3 to 4.1 years) at the time of
the first sequestration event and a median age of 2.6 years
(range, 0.8 to 5.3 years) at the time of splenectomy. The
median interval from first sequestration to splenectomy was
8.2 months (range, 0.6 to 44.8 months). Among the S S patients undergoing splenectomy, there was one episode of
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THE FIRST DECADE IN SICKLECELL
779
DISEASE
a
1o.81
I::
0.6
E 0.4 -
r
02
E 0.4
c
, A
y
W
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1.0
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3
4
5
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7
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21
30
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ss
-
l
-
0.0
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5
B
SB+
10.2
0.0 1
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SBo
6
7
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Age at Rrst WMUl cltsll,(9)
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AgnatflrstAcuteChsatsyndmne(yn)
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cp
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1
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2
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.
.
1
.
.
.
.
.
.
.
2
3
4
5
6
7
8
9
Age at !%
Acute
l Anemic E r n Norrspbnic(ym)
.
9
.
.
1
0
1F
:
F
0.9
0.8
1
I
-
0
.
3
4
5
6
7
8
AQS at Flm BMnsmieEvent (yn)
.
.
.
1
0
0
.
1
.
2
.
3
Age at
.
4
.
5
m
.
6
.
7
8
.
.
.
9
1
0
(m)
Fig 1. Age at first clinical eventin patients with sickle cell disease, from birthto 10 years of age. (A) Painful event.(B) Acute chest syndrome.
(C) Hand-foot syndrome (dactylitis).(D)Bacteremia. (E) Acute anemic events not including splenic sequestration. (F) Splenic sequestration.
bacteremia ( S viridans) in the months before splenectomy
and none in patients after splenectomy.
Acute anemic episodes were rare in SC children; 7 children had 10 events, 8 of which were caused by splenic
Table 3. Comparison of Event Rates (Cases per100 Person-Years)
in Hb SS Patients With and Without a Thalassemia
SS
(n = 2101
~~
.2179
Painful event
43.27
27.63
Acute chest
20.08
26.96
Bacteremia6.00
4.49
Splenic sequestration
.g291 3.73
3.63
Other anemic events
2.07 4.30
CVA
1.15
SS + a
Thalassemia
(n = 100)
~~~
P Value
~
<.0001
a120
0.00
a324
B186
sequestration. None of these patients required splenectomy.
One S$ thalassemia patient had splenectomy at the age of
7.2 years after three sequestration episodes, the first occuring
at 5.6 years of age.
Mortality. Twenty children, all with Hb SS, died during
the study period, for an overall incidence of 1.1 per 100
person-years. The mortality rate was highest between 6
months and 3 years of age (Fig 3). Eleven children died
from infection (9 S pneumoniue and 2 H injuenzue), 1 from
an infarctive CVA, 2 from acute splenic sequestration, and
6 from unclear causes. Of these 6 who died from unclear
causes, no information is available for 1 patient. Autopsies
were performed on 2 of the others. A 6-month-old found
dead in bedwas classified as a sudden-infant-death syndrome, although no cultures were perf0rmed.A 2-year-old
who collapsed while playing was found to have pulmonary
congestion and some splenic enlargement. Autopsies were
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GILL ET AL
780
Table 4. Bacteremic Events in SS and SC Patients
Total Organism
BoneiJoint
Meningitis
No. of
Chest
Cases Acute
Bacteremla
Isolated
S pneumoniae
H influenzae
ss
sc
ss
sc
sc
ss
sc
S viridans
ss
sc
ss
sc
Other
14 ( 1 )
8* (2)
3
0
1
3
2
2
0
2
1
4
1
0
0
1
0
0
0
1
0
0
1
0
0
0
0
2
1
l*
0
0
0
I§
0
1
0
0
0
0
0
0
1
0
1
3
1
5
2
3
2
2
0
SCt
Salmonella
sp
9
6 (2)
2
5
ss
E coli
39 (6)
12
10
4
5
1
ss
S aureus
62
1
0
1
0
1
1
The numbers in parentheses are the number of deaths.
* T w o of eight patients had concurrent pulmonary infiltrate (acute chest syndrome).
t One SC patient had E coli bacteremia with a urinary tract infection.
t Enterobacter.
§ H parainfluenza.
notperformedon
theremaining 3 children, and cause of
death could not be determined clinically. A l-year-old child
visitingHaiti became unconsciouswhileplaying
andwas
dead on arrival at the local hospital. A 2-year-old child had
vomiting and diarrhea for 2 days, then had a seizure,
was
comatose on arrival at the hospital, and was declared
to be
Achest
brain dead after 4 daysonlifesupportsystems.
radiograph showed right pleural effusion and density.A 2.5year-old had fever for 1 day followed by lethargy and coma
and died in the emergency department.
Red blood cell transjiusions. Red blood cell transfusions
were frequentlyadministered to Hb SS patients: 35% had
received a transfusion by the age of 5 years compared with
only8% of Hb SC patients. Among the Hb SS patients,
356 (48.7%) of the transfusions were administered for acute
(51 3 % ) wereadministeredas
pal-t ofa
eventsand407
chronic transfusion program. No standard criteria for transfusionwere set by thestudy. In Hb SS patients the most
common acute indications for transfusion were acute anemia
(34.6%), acute chestsyndrome(27.5%), infection (9.8c?r),
. ......
..
..
..
..
3.14
. ..
..
1.00
1979
1980
1981
1982
1983
1984
YEAR
1985
1986
1987
1988
.
Fig 2. Rates of Spneumoniae
and H influenzae bacteremia and
mortality caused by bacteremia
in patients with sickle cell anemia who are 6 months to4 vears
of age. 11.
Incidence of bacteremia;(a) incidence of mo,.tality
caused by bacteremia.
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THE FIRST DECADE IN SICKLE CELL DISEASE
781
1 .0
.......................................................
.>_..
L.
...
................................
.........................
\___
->
0.9
$
0.8
~
6
12
c
0
P
E
8
0.7
e
n
0.6
0.5
Fig 3. Mortality in children
with sickle call anemia. Ninetyfive percentconfidencebands
are shown.
l
0.5
0.0
3.5
I
3.0
I
2.5 1.02.0
and surgery (9.8%). Treatment of CVA was the indication
for only 5.6% of acutely administered transfusions but accounted for 60.2% of those administered on a long-term
basis. The second most frequent indication for chronic transfusion therapy was for prevention of recurrent anemic episodes.
DISCUSSION
The longitudinal study of the children in this infant cohort
yields important information about the type and severity of
events encountered by infants and young children with sickle
cell disease. The advantages of this cohort study are the
large number of children enrolled, the entry of all study
subjects before 6 months of age, the inclusion of patients
from a number of centers, and the prospective collection of
data on virtually all significant events.
As previously described,8"' the children with SS and SO'
thalassemia in our study have had a more severe disease
course than have those with SC and Sp' thalassemia. The
most frequent events for all four genotypes are the painful
crisis and the acute chest syndrome. In contrast, the handfoot syndrome and acute anemic episodes occur frequently
only in SS and Sgo thalassemia children. Painful crises and
the hand-foot syndrome rates in the study are certainly lower
than the true incidence because only episodes for which the
parents sought medical care were recorded.
Those clinical events which result from cumulative organ
damage were infrequent in this young cohort. Although
cerebrovascular accidents occurred as early as 2 years of
life, this complication was rare in the cohort: 13 events in
SS patients and none in SC or S o thalassemia patients. The
highest incidence (2.0 per 1 0 0 person-years) occurred in
the 6 to 7 years of age SS group. An overall incidence of
approximately 8% has been reported in other studies."," In
a study of patients in Los Angeles conducted over a 25-year
period, the overall incidence of stroke was 8.8% in 785 SS
patients and 3.0% in 231 SC patients. However, the median
l
l
I
I
1.5
I
I
4.05.0
I
I
4.5
Age at Death (yrs)
age at first CVA was 13.1 years in SS patients (range, 0.6
to 47.1 years) and 47.2 years in SC patients (range, 8.9 to
64.4 years)." In the Jamaican cohort study, 7.8%of patients
had experienced a CVA by 14 years of age (median age, 6
years and 3 months; range, 15 months to 14 years)." The
incidence of CVA in our newborn cohort is expected to
increase as the cohort ages. The extension study of this cohort now in progress will provide needed data about uncommon events and about those caused by cumulative organ
damage.
Significant complications occurred in the first 6 months
of life: bacteremia and splenic sequestration in SS patients
and acute chest syndrome in SS and SC patients. Bacteremia
was most frequent during the first 3 years of life in Hb SS
children. The mortality rate was high from bacteremia in the
SS patients in this age group (15.6% mortality in S pneumoniae infections and 22.2% in H injluenzae infections).
In Hb SC patients, bacteremia occurred most frequently
during the first 2 years of life, as was previously reported
for the young SC patients in the entire CSSCD." The frequency of Spneumoniae and H injluenzae type B bacteremia
in our SC cohort is higher than that reported for normal
children seen in "walk-in" clinics in this ~ountry.'"'~
In a
Jamaican cohort observed from birth, SC patients had serious
infections at twice the rate of concurrently observed children
with hemoglobin AA.L6
In contrast to the high mortality rate in the SS patients,
none of the infections in SC or Sp+ thalassemia patients in
this cohort were fatal. The infections in SC children appear
to have been less fulminant andor more amenable to treatment than those in SS patients, perhaps because of the longer
preservation of splenic function in SC patients.l7 However,
fatal infections do occur in SC patients.
Mortality in this infant cohort (1.1 deaths per 100 personyears for SS patients and 0 for other genotypes) is lower
than that previously reported.8,'0,18-20
In a large patient group
observed longitudinally in Los Angeles for the 25 years
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
782
preceding 1990, the death rate in the first 5 years of life was
about 3 per 100 person-years for SS patients and about 0.4
for SC children. The rate decreased dramatically in the 5to 9-year-old patients to about 0.8 per 100 person-years for
SS patients and to 0 for SC patients.”
In the cohort of Jamaican newborns, 13% of the SS and
5% of the SC children died by 2 years of age. In this Jamaican cohort, the deaths that occurred in SS children less than
6 months of age and all deaths in SC children were from
diseases common to normal children and not related to the
sickling disorder. In contrast, 10% of the Jamaican SS patients died between 6 and 12 months of age from infection
or acute splenic sequestration. Children in the Jamaican cohort with fatal splenic sequestration died outside the hospital
or within a short time of admission.2’ In the cohort study
presented here, only two deaths were caused by splenic sequestration. Education of parents about this complication
and the need for early medical treatment combined with the
frequent use of red blood cell transfusions may explain the
lower mortality rate from splenic sequestrations in our cohort.
The low mortality rate in our cohort is due to multiple
factors, including improvements in medical care, early identification and enrollment of affected infants in sickle cell
treatment centers, parent education about serious complications and about the importance of seeking immediate medical
care, and immediate antibiotic treatment for febrile illnesses.
A randomized, placebo-controlled study showed the efficacy of twice-daily oral penicillin in decreasing mortality
from S pneumoniae infections in SS patients.” Penicillin
prophylaxis became standard in participating centers after
the study results were published in1986. Although there
were fewer infections with Spneumoniae and no deaths from
infection in our cohort after 1986, the difference was not
statistically significant compared with the earlier period. The
protective effects of penicillin may have been obscured for
several reasons. Two centers had used penicillin prophylaxis
routinely and some selectively since 1978, the beginning of
the cohort study. The number of person-years of observation
for young children (those less than 2 years of age) was also
lower in the last few years of the study and may have been
too low to observe protective effects of penicillin prophylaxis.
In a large patient population observed in Los Angeles,
233 SS children less than 6 years of age had been observed
for 781 person-years by 1980.23Although none of the children received pneumococcal vaccine or penicillin prophylaxis, the mortality rate from Spneumoniae sepsis decreased
from 75% before July 1972 to 0% after that date, and the
mortality rate from S pneumoniae meningitis decreased from
65% to 18% in a comparable period. The overall mortality
rate of 14.5% from all S pneumoniae infections in our newborn cohort is similar to that of the Los Angeles post-l972
experience. The use of penicillin prophylaxis and the age of
polyvalent pneumococcal vaccination was variable in our
cohort.
The immunization of infants with conjugated H influenzae
B vaccines was introduced after the period of observation
reported here. These vaccines have dramatically decreased
the incidence of invasive H influenzae B infections in normal
GILL ET AL
children and should help decrease morbidity and mortality
in patients with sickle cell disease. The extension study now
in progress should provide better information about the protective effects of prophylactic penicillin therapy andthe conjugated HIB vaccine. A conjugated polyvalent pneumococcal vaccine is now under development.
The effects of a thalassemia on sickle red blood cells are
well k n ~ w n .The
~ ~ clinical
. ~ ~ effects of this interaction have
been more difficult to ascertain. It has been reported that
coexisting a thalassemia increases the incidence of certain
complications of sickle cell disease, such as aseptic necrosis
and proliferative retinopathy. In the analysis of painful crises
from the CSSCD, increased hematocrit and lower fetal hemoglobin levels were associated with anincreased frequency
of painful events, but no independent effect of coexisting CY
thalassemia was found.26In a longitudinal study of patients,
those with S S - a thalassemia had significantly different risk
of events for only two categories of complications. The relative risk for soft tissue events (eg, renal, central nervous
system, and leg ulcers) was significantly lower, the relative
risk being .33 with 95% confidence interval of .17 to .61.
Urinary tract infections also were significantly less common,
with a relative risk of .61 and a 95% confidence interval of
.37 to .97. No difference existed in the risk for other events,
such as painful crisis or acute chest syndrome.“’
In this newborn cohort, the SS patients with a thalassemia
had a higher incidence of painful crises than did those without a thalassemia but had lower incidences of acute chest
syndrome, acute anemic events that were not splenic sequestration crises, and transfusion. All CVAs occurred in Hb SS
patients without a thalassemia, but the number of events
was small. More experience with larger numbers of young
children will be needed to determine the possible effects of
a thalassemia on clinical events in Hb SS patients.
Life expectancy, especially in the early years of life, has
improved significantly for children with sickle cell disease
as medical care has improved and as deaths from infection
have decreased. Newborn screening, parent education, early
institution of penicillin prophylaxis therapy, and careful
medical attention are essential for prevention of early mortality. Further improvement in the quality and length of life
will depend on the prevention of chronic organ damage.
New drug therapies and the judicious use of bone marrow
transplantation may offer such improvement in the lives of
patients with sickle cell disease.
APPENDIX
The following were senior investigators in the CSSCD:
Clinical centers: L. McMahon, Boston City Hospital (Boston, MA); 0. Platt, Children’s Hospital (Boston, MA); F.
Gill, K. Ohene-Frempong, Children’s Hospital (Philadelphia, PA); G. Bray, J. Kelleher, S. Leikin, Children’s National Medical Center (Washington, DC); E. Vichinsky, B.
Lubin, Children’s Hospital (Oakland, CA); A. Bank, S. Piomelli, Columbia Presbyterian Hospital (New York, NY); W.
Rosse, J. Falletta, T. Kinney, Duke University (Durham,
NC); J. Smith, Y. Khakoo, Harlem Hospital (New York,
NY); R. Scott, 0. Castro, C. Reindorf, Howard University
(Washington, DC); H. Dosik, S. Diamond, R. Bellevue, Interfaith Medical Center (Brooklyn, NY); W. Wang, J. Wili-
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
THE FIRST DECADE IN SICKLECELL
703
DISEASE
mas,LeBonheurChildren’sHospital(Memphis,
TN);A.
Brown, S. Miller, R. Reider, P. Gillette, State University of
New York Downstate Medical Center (Brooklyn, NY); W.
Lande, S. Embury, W. Mentzer, San Francisco General Hospital (SanFrancisco,CA);
D. Wethers, R. Grover, St.
Luke’s-Roosevelt MedicalCenter (New York, NY); M.
C.
Koshy, N. Talishy, University of Illinois (Chicago, E);
Pegelow, J.D. Temple, P. Klug, University of Miami (Miami,
m);H. Zarkowsky, Washington University (St Louis, MO);
IL);H.
C. Dampier,WylerChildren’sHospital(Chicago,
Pearson, A. Ritchey,YaleUniversity (New Haven,CT);
Statistical Coordinating Centers: P. Levy, D. Gallagher, A.
Koranda, Z. Floumoy-Gill, E. Jones, University of Illinois
School of Public Health (Chicago, IL; 1979-89); S. McKinlay, 0. Platt, D. Gallagher, D. Brambilla,and L. Sleeper,
New EnglandResearchInstitutes(Watertown,MA;19891995); M. Espeland,Bowman-Gray School of Medicine
(Winston-Salem, NC); Program Administration: M. Gaston,
C. Reid, and J. Verter,NationalHeart,Lung,and
Blood
Institute (Bethesda, MD).
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From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
1995 86: 776-783
Clinical events in the first decade in a cohort of infants with sickle
cell disease. Cooperative Study of Sickle Cell Disease [see
comments]
FM Gill, LA Sleeper, SJ Weiner, AK Brown, R Bellevue, R Grover, CH Pegelow and E Vichinsky
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