Journal of Pediatric Psychology, Vol. 25, No. 5, 2000, pp. 309-322
© 2000 Society of Pediatric Psychology
Declining Immune Function in Children and Adolescents With Hemophilia and HIV Infection : Effects on Neuropsychological Performance
1 University of Texas Medical, School, Houston, 2 University of Iowa College of Medicine, 3 Emory University, 4 Tulane University Medical Center, 5 University of California, San Diego, 6 Rice University, 7 Children's Hospital of Orange Country, 8 University of Texas Health Science Center, San Autonio, 9 Rho, Inc., Chapel Hill, North Carolina
All correspondence should be sent to Katherine A. Loveland, Center for Human Development Research, Department of Psychiatry and Behavioral Sciences, University of Texas Medical School, Houston ; U. T. Mental Sciences Institute, 1300 Moursund Street, Houston, Texas 77030. E-mail : klovelnd{at}msi.uth.tmc.edu
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Abstract |
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Objective : To determine whether declines in immune functioning are associated with changes in neuropsychological performance in children and adolescents with hemophilia who are infected with the human immunodeficiency virus (HIV).
Methods : Participants were 333 males with hemophilia, ages
6-19 years at entry. A baseline and four annual neuropsychological evaluations
were given. A longitudinal growth curves analysis of data was performed to
detect changes associated with declining immune function. The cohort was
stratified into four groups : (1) HIV- (n = 126) ; (2) HIV+, average
of first two and last two CD4 counts 
200, (n = 106 ; High CD4
group) ; (3) HIV+, average first two counts 200, average last two counts
<200 (n = 41 ; CD4 Drop group) ; and (4) HIV+, average first two
and last two counts <200 (n = 60 ; Low CD4 group).
Results : There were significant differences among the four groups over time in nonverbal intelligence, perceptual/performance skills, nonverbal memory, academic achievement, and language. The Low CD4 group consistently showed the greatest decrement in performance. On measures showing a practice effect for repeated measurements, the Low CD4 group participants' scores remained stable over time, suggesting opposing effects of practice and HIV-related declines. Lowered academic performance relative to IQ was found in all groups.
Conclusions : Declines in neuropsychological functioning are directly related to declines in immune functioning in HIV+ children, adolescents, and young adults with hemophilia. Hemophilia itself may be a risk factor for academic underachievement.
Key words: human immunodeficiency virus (HIV); hemophilia; children and adolescents; neuropsychology.
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Introduction |
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Although the exact pathogenetic mechanisms of the human immunodeficiency virus (HIV) in influencing neurological and behavioral development are not well understood, children infected with HIV display a range of neurobehavioral deficits (Belman, 1992
).
Children with vertically transmitted HIV infection may have varying courses of
illness, including both static and progressive encephalopathies as well as
periods of normal development (Belman,
1994 ; Blanche et al.,
1990). Some children have early onset of both HIV-related illness
and developmental delays at less than 1 year of age ; these children have a
poor prognosis for survival. Other children have a later onset of both illness
and developmental delays and may survive well into the school-age years. Much
less is known about the developmental course of children, such as those with
hemophilia, who were infected postnatally through transfusion or other means,
or about the effects of HIV disease on older children and adolescents
(Loveland & Stehbens,
1991). In many studies, transfusion-infected children have been
grouped together with vertically infected children, who may be younger as well
as different in mode of infection and associated risk factors. Children
infected by transfusion are thought to have a more protracted course of
disease than those who were infected vertically
(Cohen et al., 1991 ;
Loveland et al., 1994 ;
Medley, Anderson, Cox, & Billard,
1987), much as do adults with HIV infection.
Although the number of children infected with HIV is increasing, the number
who acquire it through transfusion has greatly decreased since the mid-1980s
when testing for HIV in the blood supply became widely used. From the 1970s
through the mid-1980s, however, numerous individuals with hemophilia became
infected through infusion with contaminated blood clotting factor
(Brookmeyer & Goedert, 1989
; Lusher & Warrier, 1991).
Children and adolescents from this cohort have been followed prospectively and
longitudinally by the Hemophilia Growth and Development Study (HGDS) since
1989, using a multidisciplinary evaluation to examine effects of HIV infection
on neurodevelopment.
The HGDS cohort is important for several reasons. Unlike most children and
adolescents with HIV infection, HIV+ participants in the HGDS have only
transfusion-associated HIV infection and thus lack the confounding
psychosocial and medical risk factors commonly associated with vertical
transmission of HIV. In addition, the cohort studied in this large multicenter
study is multiethnic and representative of the population from which it was
sampled (Hilgartner et al.,
1993).
Most important, because the HGDS cohort children were infected with HIV
postnatally, their developmental course may differ from that of persons
infected perinatally, when the brain's rate of growth is higest.
Neurobehavioral development has been shown to be affected differently by brain
insults received at different ages. For example, the age at which neurotoxic
treatments are given to children with medulloblastoma has been found to be a
determinant of neuropsychologic outcome
(Mulhern et al., 1998).
Studies of the effects of viral infection on neurobehavioral development also
indicate that age at infection is important to outcome because of differences
in stage of brain development when infection takes place
(Rubin, Bautista, Moran, Schwartz, &
Carbone, 1999). This fact may help to account for differences in
structural brain abnormalities observed between vertically infected children
and transfusion-infected children, who are typically older at time of
infection (Brouwers et al.,
1995).
At baseline, most HGDS participants with HIV (about 90%) did not meet the
1987 Centers for Disease Control (CDC) surveillance definition for AIDS (CDC,
1987). There were no
significant differences in neuropsychological performance between the HIV+ and
HIV seronegative (HIV-) groups at baseline
(Loveland et al., 1994). About
25% of the participants had below-average neuropsychological performance, but
mean test scores were within the average range for both groups. Academic
achievement and adaptive behavior scores, by contrast, were lower than
expected for age in both groups. In addition, baseline CD4 cell counts in the
HIV+ participants were not significantly related to neuropsychological
performance, and thus it was concluded that lowered performance in academic
achievement and adaptive behavior were likely related to hemophilia itself.
These results were consistent with those of some other studies of young
persons with hemophilia and HIV infection (cf.
Sirois & Hill, 1993 ;
Whitt et al., 1993). Further
analyses have helped to elucidate this relationship within the HGDS cohort.
Those participants with a history of academic problems, head trauma, and lower
level of parent's education were found to have lowered performance on
neuropsychological measures at baseline
(Sirois et al., 1998). Of the
measures taken from the HGDS neurological examination, only coordination and
gait abnormalities were associated with lowered neuropsychological performance
at baseline and in later follow-up (Usner
et al., 1998). Because these findings did not differ for
participants with and without HIV infection, it was again concluded that
differences in findings from expected population values most likely
represented effects of hemophilia rather than HIV (cf.
Woolf et al., 1989). Other
studies of neuropsychological performance in young people with hemophilia and
HIV have also found little difference in performance related to HIV infection
at baseline, when few had symptomatic HIV disease
(Whitt et al., 1993).
In contrast to most cross-sectional studies, some studies examining
progress of disease have shown relationships between HIV serostatus or immune
compromise and neurodevelopmental outcome in persons with hemophilia. Reidel
et al. (1992), in a study of
adults with hemophilia divided by disease stage, found that deficits in
psychomotor speed, attention, and verbal learning were increasingly likely
with greater degree of immune suppression. Sirois and Hill
(1993) found, in a 2-year
longitudinal study of boys with hemophilia ages 6 to 16 at entry, that whereas
HIV- participants had improved scores over time on the Wechsler Intelligence
Scales, HIV+ participants did not. This effect was stronger for those who were
infected at younger ages. A study using laboratory measures to compare
attention in a subset of HIV+ and HIV- participants in the HGDS
(Watkins et al., 1999) at 6 to
12 months past baseline found an increased rate of false alarms on a
continuous performance test in participants with HIV infection. This finding
suggested that subclinical changes in neuropsychological performance may have
been present in HIV+ participants earlier in the follow-up than was previously
supposed.
Additional data from the HGDS indicate that HIV serostatus and measures of
immune compromise are related to physical growth and development as well as
mortality in young persons with hemophilia. Gertner et al.
(1994) found children and
adolescents with hemophilia and HIV infection had shorter stature, slower
growth velocity, and delayed skeletal and sexual maturation. Hoots et al.
(1998) found that CD4 cell
count, a measure of immune functioning, was a significant predictor of
survival among HIV+ participants at 5 years from baseline. When results were
adjusted for differences in CD4 cell count, the only baseline measure
associated with HIV-related mortality was nonhemophilia-related muscle
atrophy. These findings indicate that in the HGDS sample, HIV serostatus and
advancing HIV disease are linked both to developmental delays in growth and
maturation and to mortality.
This article reports longitudinal neuropsychological results from the HGDS, including IQ, verbal skills, perceptual performance skills, memory, fine motor, and academic achievement in relation to HIV-related immune dysfunction over 4 years. Findings on attention/concentration and on behavioral/emotional development are reported separately. We hypothesized (1) that neuropsychological outcome varies with the chronological age of the HIV-infected individual at entry into the study and (2) that developmental slowing or declines in neuropsychological functioning are directly related to declines in immunological functioning in HIV+ young persons with hemophilia.
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Method |
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Participants
A fuller description of HGDS sampling procedures is presented in Hilgartner et al. (1993
) and Stehbens et
al. (1997). Young males with
hemophilia, ages 6-19 at entry (N = 333) were enrolled in the
Hemophilia Growth and Development Study. Of these, 207 had HIV infection
(HIV+) and 126 did not (HIV-). Most participants had severe hemophilia,
defined as <1% clotting factor (74.0%) ; 19.3% had moderate hemophilia (1%
to 5% clotting factor), and 6.7% had mild hemophilia (>5% clotting factor).
Ethnic minority enrollment was as follows : 15.0% Hispanic ; 10.8% African
American ; and 1.8% other. Sixty-two percent of the nonminority participants
were HIV+ and 63% of the minority (combined) participants were HIV+. These
results have been found to be representative of the hemophilia population
identified in the study census at each participating center
(Hilgartner et al., 1993). Potential participants were excluded if they had a history of severe developmental disorder (e.g., autism) or significant psychiatric disorder (e.g., schizophrenia, bipolar disorder). All participants were required to be proficient in English so that they could be tested using English-language instruments.
At entry into the study, HIV+ participants were significantly older on
average than the HIV- group (M = 13.2 and 11.1 years, respectively)
and were more likely to have been in remedial special education at some time
(Stehbens et al., 1997). The
groups did not differ in mean socioeconomic level, parental education,
developmental history, proportion of ethnic minorities, or in severity of
hemophilia.
At baseline, the HIV+ group had lower mean CD4 cell counts than the HIV- group (61.7% HIV+ compared with 10.3% HIV- <500/mm3). Sixty-eight (33.3%) of the HIV+ participants were taking antiretroviral medication (primarily AZT). Because the HGDS is a natural history study not designed to answer therapeutic questions, we were unable to examine effects of medication treatment on outcome. The HIV+ group was relatively healthy, however, with most not meeting CDC criteria for AIDS.
Procedures
Study visits were conducted at 14 comprehensive hemophilia treatment
centers in the United States. At baseline each participant received a medical
evaluation, and extensive developmental, educational, psychological, and
neurological histories were taken. (See Hilgartner et al.
[1993] for description of
immune, growth/endocrine, neurological, and radiological studies.)
Neuropsychological data reported here are derived from a broad,
age-appropriate neuropsychological battery given at baseline and four annual
follow-up points. Medical and neurological studies were also done at annual
follow-up points but are not reported here. The neuropsychological battery
assessed seven areas of functioning : general intelligence (Wechsler
Intelligence Scale for Children, Revised [WISC-R ;
Wechsler, 1974], or Wechsler
Adult Intelligence Scale, Revised [WAIS-R ;
Wechsler, 1981] : Full Scale
IQ, Verbal IQ, Performance IQ) ; memory (Benton Visual Retention
Test, [BVRT ; Benton,
1974],* Rey Auditory-Verbal Learning Test [Rey, 1964],
the Color Span Test [Lindgren &
Richman, 1984],* WISC-R/WAIS-R : Digit Span Subtest) ;
language (Word Fluency [F-A-S]-Spreen-Benton Aphasia Battery
[Gaddes & Crockett, 1975],
Boston Naming Test [Kaplan, Goodglass,
& Weintraub, 1983], WISC-R/WAIS-R : Vocabulary Subtest) ;
visual/spatial perception (Beery Visual-Motor Integration Test [VMI ;
Beery, 1989], Performance IQ,
Judgment of Line Orientation [Benton,
Hamsher, Varney, & Spreen, 1983] ; academic
achievement (The Wide Range Achievement Test-Revised, WRAT-R,
[Jastak & Wilkinson,
1984], Kaufman Assessment Battery for Children :
Reading/Understanding Subtest [K-ABC ;
Kaufman & Kaufman,
1983]*) ; and fine motor skills (Grooved
Pegboard Test [Knights & Norwood,
1979], Trail-Making Test : Trails A, Trails B [Reitan-Indiana
Neuropsychological Test Battery for Children ;
Reitan, 1971].*
Several additional measures were given to a subset of the HGDS sample enrolled
in six Intensive Neuropsychological Follow-up (INF) centers within the HGDS.
These additional measures (shown with asterisks, above) were also given to
those who met HGDS criteria for suspected declines in any area of follow-up
("triggering"). For triggering, approximately a 1 standard
deviation drop in score in any area tested was required
(Loveland et al., 1994). In
interpreting these additional measures, one should remember that only a subset
of HGDS participants received them. A more complete description of
neuropsychology procedures for the HGDS is given in Stehbens et al.
(1997).
Statistical Methods
The cohort was stratified into four groups based on HIV serostatus and
trajectory of semi-annual CD4 cell counts, in order to capture an increasing
level of immune dysfunction. Because the criterion of CD4 cells/mm3
<200 has been used to define severe immune dysfunction associated with AIDS
(CDC, 1987), we defined the groups as follows : (1) HIV- (n = 126 ;
HIV- group) ; (2) HIV+, average of first two and last two CD4 + counts 200
(n = 106 ; High CD4 group) ; (3) HIV+, average of first two counts
200, average of last two counts <200 (n = 41 ; CD4 Drop group)
; and (4) HIV+, average of first two and last two counts <200 (n =
60 ; Low CD4 group). Table I
shows vital status of each group at four years.
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Most of the attrition due to death occurred among HIV+ participants who enrolled with a low CD4 cell count. Missing data due to deaths or dropout among the four HIV/CD4 groups have implications for the statistical analysis. If the likelihood of censoring (data loss) is related to the underlying rate of change in the outcome variable, the censoring is termed "informative." Methods used in this analysis assume that all missing data are missing at random and so do not adjust for potential informativeness of the missing data. Thus, estimated rates of change in the outcome variable could be biased due to informatively censored data, with the degree of bias related to the extent to which data are informatively censored within each group. As a result, one would expect that estimates for the Low CD4 group have the greatest likelihood of bias due to the relatively large proportion of deaths that occurred in that group. The effect of this bias would be to remove from the data set the most severely affected individuals, which could underestimate the degree of neuropsychological decline present in the Low CD4 group over time. Thus, the effect of any informative censoring on results of these analyses would likely be conservative with respect to our hypotheses.
A longitudinal analysis of data was performed for each of the neuropsychological outcomes measured at baseline and four annual follow-ups to examine whether there were changes associated with HIV status and declining immunologic functioning in HIV + participants. Group differences in trajectories of development were addressed by comparing linear and quadratic growth curves for each outcome measure. Both raw scores (RS) and standard scores (SS) were analyzed when available, in order to examine changes in scores reflecting absolute levels of skills as contrasted with age-standardized scores. Separate growth curves were fit to the repeated measurements of each outcome within each of the four HIV/CD4 groups. The following covariates were included to control for factors associated with neuropsychological functioning : age at baseline, parents' education level, history of academic problems, slowness to speak, and head trauma before or during the period of study.
Because testing was administered repeatedly over the period of study, a
time-varying indicator variable for "test transition effect" was
included as a covariate in analyses of data from the WISC-R/WAIS-R and the
WRAT-R. Both the Wechsler scales and the WRAT-R are age-normed, and a
different test is administered to older than to younger participants (age
cutoffs <17, 17 for the WISC-R/WAIS-R, respectively ; <12, 12
for the WRAT-R Levels I and II, respectively). Preliminary analyses revealed a
potentially significant test transition effect whereby inflated scores were
attained on subtests administered repeatedly, as shown by a drop in scores the
first time the new version of the test was given.
Preliminary analyses also investigated the possibility of including two
additional covariates in the analyses, estimated time since HIV infection and
chronological age at estimated time of HIV seroconversion, in order to
determine whether chronological age mediates the effect of HIV infection
(i.e., whether age at which infection occurs is important in determining
outcome) and also to determine whether individuals infected with HIV for
longer periods of time are more likely to have declining neuropsychological
functioning. Methodologic difficulties arose in consideration of these
variables for group comparisons, however, because they pertained only to the
HIV+ participants, and the includsion of the HIV- participants was considered
essential to the interpretation of the data. Exploratory analyses using only
the HIV+ cohort found that time since seroconversion was not significantly
associated with neuropsychological functioning. This finding was not
surprising, since the great majority of the HIV+ cohort was infected within
roughly the same 18-month period, so that there was little variability in time
of infection and thus little opportunity to detect an effect of the amount of
time since infection. Other studies have found that time since infection is
not related to outcome once results are adjusted for level of immune
dysfunction (e.g., Wilkie et al.,
1992). As a result of the relatively small window of time within
which most HIV+ participants became infected, age at estimated time of
seroconversion was highly correlated with age at baseline in the HIV+ groups
(r =.96), preventing the estimation of separate effects for age at
baseline and age at seroconversion. Thus, although age at baseline was
included as a covariate in the growth curve modeling, we also included an
interaction between HIV serostatus (positive/negative) and age at baseline,
with the assumption that a differential effect of age at baseline for the HIV-
and HIV+ groups could reflect in part an effect of age at seroconversion.
Methods for the analysis of unbalanced repeated measures data were applied using the statistical package BMDP, program 5V. Goodness-of-fit of different models for the within-subject covariance matrix was evaluated using Akaike's information criterion (AIC) ; unstructured covariance matrices were found to fit best and were used throughout. For each, outcome, the best-fitting models were selected using a step-down approach considering both linear and quadratic effects of time since baseline and age at baseline. The effect of each of the dichotomous covariates was allowed to vary by time and age by including all two-way interactions between time since baseline and age at baseline. In addition, the effects of academic problems and parents' educational level were allowed to vary by HIV/CD4 category (group), and the effects of history of head trauma and age at baseline were allowed to vary by HIV serostatus. Likelihood ratio tests for goodness-of-fit were used to eliminate nonsignificant terms from the full model. Main effects of all covariates were included in the final model, unless otherwise noted. In general, other terms were kept in the model if their corresponding p values were less than.10.
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Results |
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Growth curves for all variables were adjusted for the effects of the covariates (age at baseline, test transition effect, slowness to speak, academic problems, parents' level of education, history of head trauma, and head trauma on study). Pairwise comparisons of the estimated changes over time (i.e., linear or quadratic growth curve parameters) were made to determine whether participants in the four HIV/CD4 groups were developing differently with respect to the specific outcome measures in order to test the hypothesis that immune compromise is associated with decrements in neuropsychological performance. Figure 1 illustrates the predicted growth curves for each of the HIV/CD4+ groups for representative outcome measures in the areas of intelligence, language, perceptual/performance skills, nonverbal memory, and academic achievement, including the following : WISC-R/WAIS-R Verbal and Performance IQ, Vocabulary Raw Score, and Block Design Raw Score, and for Rey Auditory Verbal Learning Test Total Raw Score and Wide Range Achievement Test-Revised, Spelling Subtest Standard Score.
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When we included both linear and quadratic effects of time since baseline
in the final model, comparisons corresponded to a two-degree-of-freedom test
of the hypothesis that both linear and quadratic terms are from the same
underlying distribution. A Bonferroni correction to the alpha level was made
to reduce the probability of a Type I error due to multiple comparisons.
Pairwise differences in the estimated growth curve parameters were considered
significant if p 
.0083 ; those with.0083< p .05
were regarded as near significant. Because of the complexity of the models,
covariate effects are summarized below. Significant differences among the four
HIV/CD4+ groups in the estimated change over time for each measure are
reported in Table II.
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Group Differences in Estimated Changes Over Time
Intelligence.
For all participants there was a clear beneficial effect of practice
(repeated testing) on nonverbal but not verbal intelligence scores. The
practice effects found in this study were consistent with those found in other
studies involving repeat testing with similar measures
(Selnes et al., 1995 ;
Stern et al., 1995). In this
study, the results were corrected for the test transition effect, where it
occurred. However, the widespread presence of this effect in our data
emphasizes the importance of examining this factor in studies using repeated
testing. Although only PIQ showed near significant differences in slopes among
groups (see Figure 1b), there
was a trend for increasing time since baseline to be associated with poorer
performance on all intelligence measures in immune-compromised individuals
with HIV infection. Absolute levels of mean IQ scores stayed within the
average range for all groups throughout the period of study, reflecting the
fact that not all individuals in the HIV+ groups experienced significant
declines in health and neuropsychological functioning.
Language.
Participants in all groups gained naming vocabulary and word fluency skills
over the period of study, but there was some evidence that not all aspects of
organized expressive language and verbal intelligence progressed for all
participants. Results for WISC-R/WAIS-R Vocabulary RS indicated significant
differences in acquisition of new skills between the HIV- group and other
groups over the period of study (see Figure
1c).
Visual/Spatial Performance.
Results suggested WISC-R/WAIS-R measures were sensitive to HIV/CD4
category. There were clear improvements in performance with repeated testing
(practice effect) for PIQ, with healthier individuals performing better over
time. In less healthy persons, especially in the Low CD4 group, this effect
may have been opposed by concurrent declines, resulting in plateauing of
scores.
Memory.
There was some evidence of decrements in both verbal and nonverbal memory
in HIV+ participants associated with advancing HIV-related illness. There were
several significant or near-significant differences in estimated growth curves
for memory over time between healthier and less healthy groups, particularly
the Low CD4 AVLT total raw score and the WISC-R/WAIS-R Digit Span raw score
increased with increasing time since baseline, indicating better performance
over the period of study in all groups.
Academic Achievement.
Reading, reading comprehension, and spelling standard scores showed clear
declines or plateauing over time for the Low CD4 group, such that participants
were not keeping up with age-mates, even though they may have been acquiring
new skills. Results for the arithmetic subtest were less clear but showed a
similar trend. There were several significant or near-significant differences
in estimated growth curves among the groups. Academic achievement standard
scores tended to be lower for all groups than would be expected based on IQ
scores, in some cases 10 to 15 points lower.
Fine Motor.
In contrast to other areas of functioning, all groups tended to perform
better over time in fine motor skills, as measured by speed of performance,
with no differences in the estimated growth curves, suggesting that these
measures were not sensitive to increasing immune dysfunction.
Additional Measures
Results of the additional measures given to a subset of the HGDS sample,
including Benton Visual Retention Test (BVRT) total errors and Color Span
total RS (memory), Trailmaking A and B (visual attention and fine motor
skills), and Kaufman Assessment Battery for Children Reading/Understanding
Subtest SS (academic achievement) were similar to those for the measures given
to the full sample. Performance tended to improve over the period of study for
all groups, but individuals with greater immune compromise improved less than
healthier individuals. The only statistically significant pairwise differences
in estimated slopes were for the K-ABC Reading/Understanding SS.
Effects of Developmental History Covariates on Outcome
The analysis of covariates was highly complex and will be summarized
briefly. Details may be obtained on request from Katherine Loveland. There was
considerable consistency in the effects of the covariates across outcome
measures and functional areas. As expected, having a history of academic
problems, slowness to speak, or head trauma was associated with poorer
performance for all groups. In a number of cases, these covariates interacted
significantly with age, such that the degree of negative effect on outcome
varied with participant's age at baseline. By contrast, higher level of
parents' education was consistently associated with better performance. In
several instances (VIQ, Vocabulary SS and RS, Reading SS), the beneficial
effect of higher parents' education was greatest for the Low CD4 group.
Greater age at baseline tended to be associated with better performance on measures of absolute skill level (raw scores) across a variety of functional areas including Language, Perceptual Performance, Memory (Verbal and Nonverbal), and Academic Achievement skills. This finding indicates that older participants had acquired more skills than younger ones at entry into the study and tended to maintain this developmental advantage over the course of the study. For some other measures, however, greater age at baseline was associated with poorer performance, either as a main effect (FSIQ, Beery VMI SS, Grooved Pegboard Dominant Hand, Benton VRT errors) or in interaction with another developmental variable. For several outcome measures, greater age at baseline was associated with poorer performance for those participants with a history of academic problems (Vocabulary RS, PIQ, Arithmetic RS), slowness to speak (Benton VRT errors), or head trauma (Grooved Pegboard Dominant hand). The above effects were similar for all four groups.
Because age at time of infection and age at baseline were highly correlated, and because effects of age at baseline did not differ by HIV serostatus, we could not infer the effect of age at infection separately from age at baseline. Thus, although we can examine effects of age on performance, we are unable to tell whether HIV-related changes in functioning varied with age at infection.
For those tests with versions for younger and older individuals
(particularly the Wechsler tests), there was often a significant test
transition effect, such that scores tended to drop when the transition was
made from the test normed for younger persons to the test normed for older
persons (i.e., when the WAIS-R was first administered after previous
observations using the WISC-R). This finding likely resulted from a practice
effect : when the test for older individuals was given, the benefit of
practice on the test for younger individuals was removed or reduced (cf.
Mulhern, Ochs, & Fairclough,
1992).
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Discussion |
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TopAbstractIntroductionMethodResultsDiscussionAppendixReferences |
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The hypothesis that neuropsychological outcome would vary with the chronological age of the HIV-infected child or adolescent at entry into the study was partially supported. Interestingly, in the HGDS sample older age at entry tended to be associated with poorer outcome on some measures, particularly in combination with other risk factors. This result contrasts with the general finding that vertically (perinatally) infected children often have shorter survival times and a shorter time before onset of neurobehavioral deficits than do transfusioninfected children. Although this result may be an artifact of the relatively small numbers of older adolescents in the HGDS, it may also reflect differences in rate of brain development between older and younger participants. Boys who were older at entry, particularly those with additional risk factors, might be more likely to have decrements in performance than younger boys, whose more rapid development would tend to offset disease-related losses.
The results of this study supported the hypothesis that declines in
neuropsychological functioning are directly related to declines in
immunological functioning in children and adolescents with hemophilia and HIV
infection. There were statistically significant differences among the four
HIV/CD4 groups in the trajectory of functioning over time in the areas of
nonverbal intelligence, perceptual performance skills, memory, academic
achievement, and language. These results are consistent with studies of adults
with hemophilia, and they suggest a subcortical dementia process
(Reidel et al., 1992).
Participants with low CD4 counts throughout the 4 years of study showed the
highest rate of decline in performance where statistically significant
differences were found. Declines may have been related to slowed information
processing and response speed (Karlsen,
Reinvang, & Frøland, 1992 ;
Martin et al., 1992) and
failure to benefit from practice (learning). On measures where a practice
effect was found, such as PIQ, the Low CD4 group participants' scores did not
improve but rather remained stable, suggesting opposing effects of practice
and HIV-related declines in functioning over time.
In a recent review, Price
(1996) summarized the
neurological deficits directly or indirectly attributed to HIV, concluding
that virtually all components of the nervous system are vulnerable. Price has
also described the AIDS dementia complex (ADC), the likelihood of which is
thought to be directly related to the severity of the immunosupression as
measured by the CD4 cell count, with ADC most often associated with CD4 cell
counts lower than 200. In general, the observed association between
neuropsychological performance and trajectory of CD4 cell counts in the HGDS
sample could reflect several factors, including not only direct effects of HIV
disease on cognition but also effects of secondary factors such as increasing
school absences due to illness and impaired performance due to illnessrelated
fatigue or anxiety (Sexson &
Madan-Swain, 1995 ; Wolters,
Brouwers, & Moss, 1995). Our findings with respect to academic
achievement are consistent with the findings of previous studies, including
the HGDS (Loveland et al.,
1994 ; Smith, et al.,
1997). Impairments of coordination and gait in HGDS participants
(Sirois et al., 1998) could
interfere with school attendance, ability to take advantage of environmental
stimulation (e.g., educational activities), and attention and concentration.
Thus, these findings further support the view that hemophilia is itself a risk
factor for lower academic achievement
(Sexson & Madan-Swain,
1995 ; Woolf et al.,
1989).
Although many studies have found differences between HIV- and HIV+
individuals in neuropsychological performance (e.g.,
Bornstein et al., 1995), recent
studies of adults with HIV infection have not always found relationships
between neuropsychological functioning and measures of immune function. Selnes
et al. (1995) in their study
from the Multicenter AIDS Cohort Study (MACS) of adult men with HIV infection
did not find significant drops in performance related to onset of clinical
AIDS ; the greatest change was a decline of 1 standard deviation in
psychomotor speed found at 2.5 years after diagnosis. No relationship was
found between CD4 cell count and neuropsychological performance, and the
authors concluded that declines in immune functioning may be necessary but not
sufficient to bring about cognitive decline. Wilkie et al.
(1992) in a cross-sectional
study did not find declines in neuropsychological functioning associated with
degree of immune dysfunction when groups were divided similarly to those of
this study, although they did find differences between HIV- and HIV+
participants as a whole on verbal and visual memory, information processing
speed, visual spatial skills, language, attention and reaction time, and
mental status. These studies differed from the HGDS in a number of ways, not
only in studying adults, but also in the use of different research designs,
assessment instruments, and variables of interest. The HGDS may have been more
sensitive to relationships between immune compromise and neuropsychological
functioning because of its longitudinal design, a longer period of
measurement, and the use of a growth curve modeling analysis.
Our results also differ from those of
Hooper et al. (1997), who
reported no differences between 25 HIV-infected and 33 noninfected children
and adolescents with hemophilia over a 2-year follow-up, and Smith et al.
(1997), who similarly reported
no differences between 19 HIV-infected and 17 noninfected children and
adolescents with hemophilia over 3 years. Because of its much greater sample
size and longer period of observation, the HGDS likely had greater power to
detect differences in development between individuals with and without HIV.
Classifying HIV+ participants according to both their HIV status and the
degree and chronicity of immune compromise provided the opportunity to detect
differences between healthier and less healthy individuals with HIV
infection.
The HGDS findings also differ in some ways from those reported for children
who were perinatally infected with HIV. As in some other studies of children
infected with HIV through blood transfusion rather than vertical transmission
(Cohen et al., 1991), HGDS
participants have typically remained free of HIV-related neuropsychological
changes for an extended time after becoming HIV seropositive. Moreover, our
results suggest that changes in neuropsychological functioning may not occur
until a sufficient degree of decline in health and immune functioning is
present. Thus, as in some other studies of children and adolescents with
hemophilia and HIV infection (Smith et
al., 1997), the pattern of early, severe declines seen in some
young children with HIV infection did not occur in HGDS participants. Although
this difference is related in part to age at infection and to mode of
transmission, it may also be related to differences in psychosocial factors
that can affect outcome. The HGDS data indicate that higher educational level
of the parents is associated with better outcome, particularly for individuals
with greater immune compromise. This finding suggests a possible
"threshold effect" (Satz,
1993) in which individuals with greater brain reserve capacity
(BRC) related to such factors as intelligence and educational opportunity are
less vulnerable to the effects of progressive brain disease until a threshold
of illness is crossed. In general, the hemophilia population lacks many of the
psychosocial risk factors that can affect children vertically infected with
HIV. For example, the severe illness or death of a parent due to AIDS is
likely for the vertically infected child but not for the child with hemophilia
and infusion-associated HIV infection. Among other possible effects,
psychosocial risk factors may affect the child's likelihood of receiving
appropriate, timely, and consistent treatment for HIV disease. Thus, if the
parents of vertically infected children are disproportionately ill or from
disadvantaged circumstances, their children will be at greater risk for poor
outcome.
Caution must be taken in interpreting the significance of the individual
outcome measure results in this study, because of the large number of
comparisons made. The consistency of these results, however, argues in support
of our conclusions, as declines in neuropsychological functioning were
associated with increasing levels of immune dysfunction for a variety of
measures. Although the HGDS is essentially a natural history study of growth
and development in young persons with hemophilia and HIV infection, 33% of
HIV+ participants were taking antiretroviral medication or other anti-HIV
therapies at baseline and 82.4% of the HIV+ sample (169/205) had done so at
some time by the fourth annual follow-up. At the time of the fourth annual
follow-up, 68.8% (86/125) of those still enrolled were taking antiretroviral
medication. Because participants received different medication regimens, and
their compliance with those regimens is unknown, it is not possible to
evaluate the effects of medication on the development and health of the HGDS
sample, except to say that it may have extended the lives of those taking it
(Wolters et al., 1995). It is
not possible to tell from these data whether trajectories of
neuropsychological development would have been different in a hypothetical
untreated group. Nevertheless, because most children and adolescents with HIV
infection who are participating in research studies currently do receive
antiretroviral medication, the HGDS findings should be comparable to findings
from other pediatric samples with HIV infection. There is a need to continue
monitoring young people with HIV such as those in the HGDS, particularly as
newer therapies such as protease inhibitors become more widely used. For
example, as viral load is reduced, neuropsychological functioning may be
stabilized or improved.
This study also supports the need for interventions to address neurobehavioral problems in children and adolescents with HIV infection. The long period of relatively healthy functioning many children with HIV now experience allows planning for the onset of plateaus or losses in cognitive, adaptive, emotional, and neuromuscular functioning. At the same time, the longer lives of children and adolescents with HIV increase the demand for services such as physical and occupational therapy and speech/language therapy, along with classroom adaptations and family supports. Although the the greatest potential for successful intervention may occur in the preschool years, the results of the HGDS emphasize that the need for these services continues through adolescence.
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Appendix |
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TopAbstractIntroductionMethodResultsDiscussionAppendixReferences |
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Funded by National Institute of Child Health and Human Development ; Bureau of Maternal and Child Health and Resources Development ; Centers for Disease Control and Prevention ; National Cancer Institute ; National Institute of Mental Health. Center Directors, Study Coordinators, or Committee Chairs : Children's Hospital Los Angeles : E. Gomperts, MD, W.-Y. Wong, MD, F. Kaufman, MD, M. Nelson, MD, S. Pearson, RN ; New York Hospital-Cornell Medical Center : M. Hilgartner, MD, S. Cunningham-Rundles, PhD, I. Goldberg, RN ; University of Texas Medical School, Houston : W. K. Hoots, MD, K. Loveland, PhD, M. Cantini, RN ; National Institute of Child Health and Human Development : A. Willoughby, MD, MPH ; New England Research Institutes, Inc. : s. McKinlay, PhD, M. Maeder, MHS ; Rho, Inc. : S. Donfield, PhD ; Baylor College of Medicine : C. Contant, Jr., PhD ; University of Iowa Hospitals and Clinics : T. Kisker, MD, J. Stehbens, PhD, S. O'Conner, J. McKillip, RN ; Tulane University : P. Sirois, PhD ; Children's Hospital of Oklahoma : C. Sexauer, MD, H. Huszti, PhD, F. Kiplinger, S. Hawk, PA-C ; Mount Sinai Medical Center : S. Arkin, MD, A. Forster, RN ; University of Nebraska Medical Center : S. Swindells, MD, S. Richard ; University of Texas Health Science Center, San Antonio : J. Mangos, MD, A. Scott, PhD, R. Davis, RN ; Children's Hospital of Michigan : J. Lusher, MD, I. Warrier, MD, K. Baird-Cox, RN, MSN ; Milton S. Hershey Medical Center : E. Eyster, MD, D. Ungar, MD, S. Neagley, RN, MA ; Indiana Hemophilia and Thrombosis Center : A. Shapiro, MD, J. Morris, PNP ; University of California-San Diego Medical Center : G. Davignon, MD, P. Mollen, RN ; Kansas City School of Medicine, Children's Mercy Hospital : B. Wicklund, MD, A. Mehrhof, RN, MSN.
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Acknowledgments |
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The Hemophilia Growth and Development Study has been supported in part by grants from the Bureau of Maternal and Child Health and Resources Development (MCJ-060570), the National Institute of Child Health and Human Development (NO1-HD-4-3200), the Centers for Disease Control and Prevention, the Laboratory of Genomic Diversity of the National Cancer Institute, and the National Institute of Mental Health. Additional support has been provided by grants from the National Center for Research Resources of the National Institutes of Health to the New York Hospital-Cornell Medical Center Clinical Research Center (MO1-RR06020), the Mount Sinai General Clinical Research Center, New York (MO1-RR00071), the University of Iowa Clinical Research Center (MO1-RR00059), and the University of Texas Health Science Center, Houston (MO1-RR02558). We thank the children, adolescents, and parents who volunteered to participate in this study and the members of the Hemophilia Treatment Centers. We also thank the members of the HGDS Publications Committee and the HGDS Executive Committee who reviewed drafts of this article.
Received August 25, 1998; revision received March 18, 1999; revision received July 21, 1999; accepted September 20, 1999
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