Journal of Pediatric Psychology, Vol. 25, No. 8, 2000, pp. 545-556
© 2000 Society of Pediatric Psychology
HIV-Associated Changes in Adaptive, Emotional, and Behavioral Functioning in Children and Adolescents With Hemophilia: Results From the Hemophilia Growth and Development Study
1 University of California, San Diego, 2 Emory University, 3 Tulane University Medical Center, 4 Rice University, 5 University of Iowa College of Medicine, 6 University of Texas Medical School, Houston, 7 University of Texas Health Science Center, San Antonio
All correspondence should be sent to Sharon L. Nichols, Department of Neurosciences, Division of Pediatric Neurology, University of California, San Diego, 9500 Gilman Drive #0935, La Jolla, California 92093. E-mail: slnichols{at}ucsd.edu .
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Abstract |
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Objective: To assess changes in adaptive, emotional, and behavioral functioning over four years in children and adolescents with hemophilia and with or without HIV infection and to evaluate the relationship of these changes to immune status.
Methods: Participants were 277 HIV-seropositive and 126 HIV-seronegative boys with hemophilia. Participants with HIV infection were divided into three groups based on trajectory of immune functioning (CD4+ cell counts) over the course of the study. Caregivers completed the Vineland Adaptive Behavior Scales and Pediatric Behavior Scale (PBS).
Results: Results showed declining Vineland Communication scores for participants with consistently poor immune functioning. These participants also started with more PBS Attention Deficit and Deviation symptoms, which then decreased more sharply than for other groups. Low CD4+ counts were consistently associated with more Health and Depression-Anxiety symptoms on the PBS. However, with few exceptions, group means remained within normal limits.
Conclusions: According to their caregivers, boys with hemophilia and HIV infection showed considerable resilience with regard to adaptive behavior and emotional and behavioral problems. However, over time changes occurred in these areas that appear to be related to immune functioning.
Key words: HIV infection; pediatric AIDS; hemophilia; children and adolescents; adaptive functioning; behavior.
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Introduction |
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The effect of human immunodeficiency virus (HIV) infection on a child's or adolescent's emotional well-being and ability to participate in school and home life has been a primary concern of caregivers since pediatric cases of HIV first appeared in 1981. Now, as improvements in medical treatments extend the lives of children with HIV, the impact of the disease on their quality of life, including the ability to function within age expectations in social and school contexts, takes on greater importance for families and service providers. Although a sizeable literature has emerged concerning cognitive development and neuropsychological functioning in these children and adolescents, relatively few empirical studies have been published on their day-to-day adaptive behavior and on their emotional and behavioral development. In addition, most of these studies have focused on children infected either during pregnancy or during labor and delivery, and less is known about children older at the time of infection.
One group with a particularly high rate of HIV infection during the early
1980s was those with hemophilia, a genetically transmitted bleeding disorder
that affects mostly males and requires infusions of clotting factor derived
from the blood of large numbers of donors. Up to 90% of patients with severe
hemophilia were infected before viral-inactivated, donor-screened concentrates
became widely available in 1985 (Brookmeyer
& Goedert, 1989
). The burdens and social stigma associated
with HIV disease add to the considerable stress associated with hemophilia for
these patients and their families. Hemophilia-related stressors can include
frequent medical procedures such as venipuncture, restrictions on sports
participation and other activities, and, in some cases, painful and disabling
joint deterioration. Patients with hemophilia who also have HIV disease face
the possibility of acquired immune deficiency syndrome (AIDS), frequently a
painful and debilitating illness, and the potential for central nervous system
(CNS) impairment, as well as additional invasive medical procedures and the
threat of death. HIV-infected children and adolescents confront social
isolation and difficulties in establishing independence. Adolescents face
their emerging sexuality with the reality of possible sexual transmission of
HIV, possibly leading to problems with development of sexual identity. Fear of
(or actual) discrimination and the potential adverse effects of the disease on
growth and maturation are additional stress issues. Finally, the families of
these youths must cope with these realities and frequently confront financial
pressures. In some cases, due to the genetic nature of hemophilia, they have
had to face these issues for more than one child or for other family
members.
One might predict that these enormous stressors would place children and
adolescents with HIV infection at risk for depression, adjustment disorders,
and other stress-related developmental psychopathology. In addition, there is
evidence that CNS disease associated with pediatric HIV can itself produce
changes in behavior and personality, as well as decreases in adaptive
functioning (Wolters, Brouwers, Moss,
& Pizzo, 1994). Nevertheless, the available studies on
behavior problems and emotional distress in HIV-infected children have shown
mixed results. Wolters et al.
(1994) examined adaptive
behavior and behavior ratings in a group of HIV-seropositive children with
symptomatic HIV disease, both vertically infected and infected through blood
products, and found global adaptive impairments, particularly in children with
HIV encephalopathy. In a study of primarily transfusion-infected children with
HIV, Bose, Moss, Brouwers, Pizzo, and Lorion
(1994) found that caregivers
rated the children as having higher than expected levels of anxiety,
particularly in later disease stages, and low social competence, although
self-reports by the children were within the normal range. Bussing and Burkett
(1993) found higher levels of
anxiety disorders in a small group of children with hemophilia and HIV
infection than in uninfected children with hemophilia, children with asthma,
or healthy children. In contrast, two studies
(Colgrove & Huntzinger,
1994; Hooper et al.,
1993) that used the Child Behavior Checklist (CBCL;
Achenbach & Edelbrock,
1983) with the caregivers of children and adolescents with
hemophilia found no differences overall between participants with and without
HIV infection, although Hooper et al. did find in exploratory analyses that,
among the younger participants (ages 6-11), children with HIV infection had
significantly higher scores on the Depression and Schizoid/Anxious scales than
did those without HIV infection. However, both of these studies included
relatively small groups of participants who were in the early stages of HIV
disease progression. Moss, Bose, Wolters, and Brouwers
(1998) reported preliminary
findings from a longitudinal study showing generally stable adjustment over a
2-year period in a sample of vertically and transfusion-infected school-age
children at varying disease stages. Drotar, Agle, Eckl, and Thompson
(1995), in a study of 183
children and adolescents with hemophilia, half of whom also had HIV infection,
found that the groups were comparable in their levels of psychological
adjustment but that the mothers of seropositive children had higher levels of
distress. However, children with an AIDS diagnosis were excluded from the
sample. In general, most previous studies have been cross-sectional and, with
the exception of Moss et al. and Wolters et al., have included largely
asymptomatic children. A longitudinal study that follows participants over a
longer time period and at all disease stages could clarify the relationship of
problems in daily functioning and emotional difficulties to disease
progression in children and adolescents. Focusing on youths with hemophilia
rather than vertical HIV infection would avoid many of the confounding
psychosocial issues, such as parental illness and drug abuse, that can
complicate studies of vertically infected children.
In this article, we report findings from the Hemophilia Growth and
Development Study (HGDS), a longitudinal, multicenter study of children and
adolescents with hemophilia designed to assess the effects of HIV on physical
growth, immunologic and endocrine functioning, neurological and
neuropsychological functioning, and social adaptation and behavioral
adjustment. At entry into the study, approximately 90% of the participants
with HIV did not meet the 1987 Centers for Disease Control (CDC) criteria for
AIDS (CDC, 1987). Thus, the
HGDS provides the opportunity to follow the progression of HIV disease from
the asymptomatic state through stages of significant immunologic decline and
to examine the effect of HIV disease progression on cognitive, adaptive, and
emotional functioning. Baseline findings for the neuropsychological component
of the HGDS, including measures of adaptive functioning, were reported in
Loveland et al. (1994). No
effects of HIV infection on cognitive functioning, as assessed by standard
neuropsychological instruments, were observed, and mean test scores were in
the average range, suggesting that asymptomatic HIV infection is not
associated with significant cognitive dysfunction in children with hemophilia.
However, participants both with and without HIV infection had lower academic
and adaptive skills than expected from their IQ scores, and caregivers
reported more behavioral and emotional problems than population norms. These
results were interpreted as the effects of living with hemophilia as a chronic
disease.
In contrast, longitudinal findings from the HGDS
(Loveland et al., 2000) have
demonstrated decreases for participants with HIV infection in some areas of
neuropsychological functioning, including language, academic achievement, and
some aspects of nonverbal skills and nonverbal memory. These decreases
occurred most consistently in the participants with the poorest immune
functioning, suggesting a direct relationship between cognitive and immune
functioning. Despite debate over the relationship between cognitive impairment
and immune system parameters such as CD4+ count in the adult literature (e.g.,
Price, 1996;
Selnes et al., 1995), the
findings from the HGDS, as well as other studies in children (e.g.,
Brouwers et al., 1995), support
the position that immunosuppression can be related to cognitive dysfunction
during development. However, few studies have examined the relationship
between measures of immune functioning and behavioral or adaptive
problems.
The primary objective of this study was to evaluate the effects of HIV disease progression over time on behavioral, social, and adaptive functioning in the HGDS sample, controlling for the potential contribution of a variety of demographic, social, and medical variables. We report the results of a 4-year longitudinal analysis of two caregiver report instruments completed by the primary caregivers of both HIV-seropositive and seronegative participants of the HGDS. This study is, to our knowedge, the first to provide a longitudinal assessment of the relationship between adaptive and emotional or behavioral functioning and immune status in such a large sample of HIV-infected children and adolescents at all stages of disease progression. Based on the literature cited above, we hypothesized that participants with increasing immune impairment would show greater declines in all areas of adaptive functioning and would show higher levels of behavioral and emotional problems, particularly depression and anxiety, as reported by their caregivers.
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Methods |
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Participants
Detailed descriptions of HGDS methodology are presented in Hilgartner et al. (1993
) and Stehbens et al.
(1997). The participants in
the HGDS were 333 boys with hemophilia who were between the ages of 6 and 19
at study entry (see Table I for
age and other demographic information). They were recruited from 14
participating hemophilia comprehensive care centers and were representative of
the 481 potentially eligible participants served by those centers with respect
to hemophilia severity, type, and ethnicity. The total eligible and
participating populations differed only in age distribution, with the highest
participation rate in children 
15 years of age and the lowest in
adolescents 
18 years of age. Two hundred and seven of the participants
were HIV-seropositive (HIV+), and 126 were HIV-seronegative (HIV-). Exclusion
criteria included the presence of severe developmental or psychiatric
disorder, blindness or deafness, serious nutritional disorders,
non-HIV-related immunosuppressive disorders or cancer, or lack of sufficient
fluency in English to enable valid neuropsychological testing
(Stehbens et al., 1997). Most
(72.4%) of the sample was Caucasian, 15% were Hispanic, 10.8% African
American, and 1.8% of other ethnic origins, with comparable percentages of
minority and nonminority subjects in both the HIV- and HIV+ groups
(Hilgartner et al., 1993). The
majority (74.0%) of the participants had severe hemophilia (clotting factor
levels <1%), 19.3% moderate (1%-5%), and 6.7% mild (>5%).
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At baseline, HIV+ participants were significantly older than the HIV- group (M = 13.2 and 11.1 years, respectively). This age disparity was addressed in the analyses by using age as a covariate (see below). The HIV+ participants had significantly lower CD4+ counts (423 cells/mm3 vs. 895 for HIV- participants, p <.0001), and 33.3% were taking antiretroviral treatment (almost exclusively zidovudine) at baseline.
The respondents for this study were the parents or primary caregivers of the HGDS participants. English was the primary language for 95% of the caregivers, and Spanish was the primary language for the other 5%. Caregiver report information from exclusively Spanish-speaking caregivers was collected by examiners fluent in Spanish.
Procedures
Assessments performed as part of the HGDS included baseline medical and
developmental histories and annual evaluations of neurologic,
neuropsychological, neuroradiologic, immune, growth, and endocrine
functioning. The neuropsychological component consisted of a comprehensive
series of measures administered annually and a briefer battery conducted
semi-annually. Two caregiver report measures were used to assess adaptive,
emotional, and behavioral functioning. The validity of the data in each
functional area was rated at the end of each testing session by the examiner
using a scale of 1 (valid) to 4 (invalid). At baseline, 7.2% of the PBS
ratings and 5.0% of the Vineland scores received ratings of 3 or 4 and were
judged invalid and excluded from analyses. The percentage of scores rated as
invalid at the follow-up visits ranged from 3.2 to 6.4 for the PBS and from
1.7 to 4.0 for the Vineland and did not differ significantly for the HIV- and
HIV+ participants. Quality control was maintained by several procedures:
training sessions for examiners before data collection began, reviews of all
individual records by the data coordinating center for errors, and review of
randomly chosen records by the Neuropsychology Committee co-chairs. Sites were
provided with detailed feedback on errors in scoring, arithmetic, and data
transfer.
The Vineland Adaptive Behavior Scales
(Sparrow, Balla, & Cicchetti,
1984) was the best caregiver report measure available for
assessing adaptive behavior at the time this study was designed and has been
widely used in research (e.g., Wolters et
al., 1994). It is administered through a structured interview by a
trained examiner and provides estimates of behavior in three domains:
Communication, including receptive, expressive, and written language; Daily
Living Skills, including personal, domestic, and community skills; and
Socialization, including interpersonal relationships, play and leisure time,
and coping skills. Age-normed standard scores (M = 100 ± 15)
were computed for each of these domains and the Composite score.
The Pediatric Behavior Scale (PBS;
Lindgren & Koeppl, 1987)
is a caregiver-completed checklist designed to assess behavior problems of
youths ages 6-16 in medical settings. A strength of the PBS for the purposes
of this study is that it measures behaviors related to physical problems and
chronic health issues not assessed in other available behavior rating scales
for children (Lindgren & Koeppl,
1987). For example, the Health scale asks caregivers to rate the
child's medication compliance and anxiety about medical procedures, as well as
a variety of physical symptoms and problems with arousal, sleep, and eating.
The checklist, which can be completed in 15-20 minutes, consists of 165 items
that caregivers are asked to rate on a 4-point scale to describe their child's
behavior during the previous 2 months. The items yield 24 individual scales
and 6 broad behavior factors: Conduct, including the Oppositional Behavior,
Aggression and Explosiveness scales; Attention Deficits, including Attention,
Impulsivity, and Hyperactivity scales; Depression-Anxiety, including Tension,
Anxiety, Self-Esteem, Depression, and Social Isolation scales; Deviation,
including Inappropriate Social Behavior, Perseveration, Variability, and
Thought Disorder scales; Health, including Arousal, Coordination, Eating,
Sleeping, Physical Problems, and Medical Noncompliance scales; and Cognition,
including Expression, Comprehension, and School Problems scales. The scale
scores are the sums of the individual item ratings for each behavior scale;
thus, higher scores indicate more severe or more frequent behavior problems.
The factor scores are the sums of the individual scale score sums of the
scales included in each factor.
Caregivers were administered the Vineland at the time of the annual neuropsychological assessment and the PBS at both annual and semi-annual visits. Data for the baseline evaluation and four subsequent years were available; thus, there were a maximum of five observations per participant for the Vineland and nine for the PBS. As in all longitudinal clinical studies, there were missing data for a variety of reasons including death of the participant, study dropout, missed study visit, or invalid data as judged by the examining psychologist at the time of the evaluation.
Statistical Methods
The participants were divided into four groups based on HIV status and the
trajectory of absolute CD4+ counts measured semi-annually over the 4-year
follow-up period. For the children with HIV, the average value of the first
two CD4+ counts and the average of the last two counts were used to assign
group membership. The four groups were (1) HIV-; (2) High CD4+ group: HIV+
with CD4+ counts consistently >200 cells/mm3; (3) CD4+ Drop
group: HIV+ with the average of the first two counts 200 and the average
of the last two counts <200; and (4) Low CD4+ group: HIV+ with CD4+ counts
consistently <200.
A longitudinal growth curve analysis was performed for each of the outcome
measures to examine whether there were differences between the four HIV/CD4+
groups in the change in functioning over the 4-year follow-up period. Methods
for the analysis of unbalanced repeated measures data were applied using the
statistical package BMDP 5V, which accommodates participants with incomplete
repeated measures data under the assumption that the missing observations are
missing at random (Rubin,
1976). These methods involve fitting a regression model in which
the outcome is the neuro-behavioral test score, the primary independent
variable is the time since baseline, and the lack of independence in the
outcome observations resulting from the repeated observations within subjects
is accommodated by modeling the within-subject covariance structure. A
square-root transformation of PBS factor scores was used in the analysis
because of skew. Separate growth curves were fit to the repeated measurements
of each outcome within each of the four HIV/CD4+ groups defined above.
Goodness-of-fit for the within-subject covariance matrix was evaluated using
Akaike's information criterion (AIC;
Akaike, 1973); unstructured
covariance matrices were found to fit best and were used throughout.
Several demographic and background variables were used as covariates in the analyses because of their potential relationship, independent of HIV status, to the outcome measures reported here. These included age at baseline, caregivers' education (highest grade completed by the head of house-hold), history of academic problems (defined as having repeated a grade or in remedial special education class at time of baseline), history of early slowness to speak, and head trauma prior to baseline or while on study. Nine subjects were excluded from the overall analyses because one or more of their covariate values were missing. Therefore, the final number of subjects potentially available for analysis was 324. The number of deaths, as expected, was greatest in the Low CD4+ Group. Mortality and subsequent missing data for this group were not thought to compromise data analysis because the likely direction of possible bias would be toward underestimating adaptive and behavioral/emotional problems, thus decreasing rather than increasing the likelihood of finding support for our hypotheses.
The best-fitting model for each of the outcomes was 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 corresponding two-way interactions. The effects of academic problems and caregiver's educational level were allowed to vary by HIV/CD4+ category, and the effects of history of head trauma and age at baseline were allowed to vary by HIV status. 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. Pairwise differences between groups in trajectories of development were addressed by comparing linear and (if included) quadratic growth curve parameters for each outcome measure. To reduce the probability of a Type I error, pairwise differences in growth curve parameters are considered significant if p <.01. Results with a.01 < p <.05 are discussed as trends.
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Results |
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Results from this analysis for each of the outcomes can be divided into two parts: those pertaining to the growth curves describing differences between the four HIV/CD4+ categories in changes in functioning over time, and results describing the effects of the eight possible covariates included in the final models. Most of the models are complex due to the large number of covariates and the presence of interaction effects. The discussion of results will focus on the differences between the four HIV/CD4+ groups over time for each measure. Covariate effects are described briefly following the presentation of group comparisons for all measures.
Figures 1,2,3,4 illustrate the predicted growth curves from the final model for each of the HIV/CD4+ categories for outcome measures that showed significant group differences. The growth curves plotted in these graphs were generated using models that adjust for a variety of covariate effects. When a particular covariate was included in the final model for an outcome, the average level of that covariate for the cohort as a whole was used in generating the predicted growth curves.
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The primary purpose of these analyses was to examine changes over time rather than absolute levels of functioning. Because of the clinical significance of lower scores, group means that fall below the 10th percentile (a standard score of 80) for the Vineland or above the 90th percentile for the PBS will be noted. Percentiles for the PBS are based on unpublished normative data (available from S. Lindgren, The Linden Press, Route 1, Box 291-L, Solon, IA 52333) for 300 boys ages 6-12. S. Lindgren also has norms for a smaller group of adolescent males similar to the norms for ages 6-12.
Vineland Adaptive Behavior Scales
Results for the Vineland domain and Composite scores reveal different
patterns of change over time for the Low CD4+ group relative to the other
three groups.
Communication. Scores in the Communication domain increased with time since baseline for HIV-participants and showed a dramatic decline for the Low CD4+ group after year 2 (Figure 1). The pairwise differences in the estimated change in score over time were statistically significant for the comparisons between the HIV- and Low CD4+ groups (p <.001) and the High CD4+ and Low CD4+ groups (p <.001) and approach significance for the CD4+ Drop and Low CD4+ groups (p =.025). The mean standard score for the Low CD4+ group at year 4 fell below 80 (79.17); all other group means remained in the average range.
Daily Living. The Daily Living score increased over time for all groups, although minimally for the Low CD4+ group. None of the pairwise differences in the estimated change in score over time was statistically significant.
Socialization. The growth curves for the Socialization score show positively sloped lines for all groups except the Low CD4+ group, who had a negatively sloped line. None of the pairwise differences in the estimated change in score over time was statistically significant, however.
Adaptive Behavior Composite. Results for the Composite score were very similar to those shown in Figure 1 for the Communication score, and the significance of pairwise differences in the estimated change in score over time were also similar (HIV- and Low CD4+ groups, p =.0099; High CD4+ and Low CD4+ groups, p =.006; and CD4+ Drop and Low CD4+ groups, p =.023).
Pediatric Behavior Scales
Results for the PBS outcomes revealed that all factor scores, except Health
Problems, tended to decrease over time, indicating fewer problems.
Conduct. Scores on the PBS Conduct Disorder factor decreased over time for all four groups (Figure 2). The difference in the estimated change in score over time between the HIV- and CD4+ Drop groups was statistically significant (p =.007), with a greater decline in the CD4+ Drop group. Note that the Low CD4+ group started out with higher scores; however, the change over time was not significantly different from that of the other groups.
Attention Deficits. Scores on the Attention Deficits factor decreased for all groups over time (Figure 3). The decrease was greatest for the CD4+ Drop and Low CD4+ groups, which began with higher scores at baseline. The pairwise differences in the change in score over time were statistically significant for the High and Low CD4+ groups (p =.010) and approached significance for the High CD4+ and CD4+ Drop (p =.019), HIV- and Low CD4+ (p =.021) and HIV- and CD4+ Drop (p =.047) groups.
Depression-Anxiety. Scores on the Depression-Anxiety factor decreased slightly over time for all three HIV+ groups and remained stable for HIV- participants. None of the pairwise differences in the estimated change in score over time was statistically significant. The Low CD4+ group had consistently higher scores than the other groups at all time points, although they remained within normal limits.
Deviation. Deviation factor scores decreased with time since baseline for all groups (Figure 4), though the decline was considerably greater for the CD4+ Drop and Low CD4+ groups who started out higher. The pairwise differences in slopes were statistically significant for the HIV- and CD4+ Drop groups (p =.005) and approached significance for the HIV- and Low CD4+ (p =.036) and High CD4+ and CD4+ Drop (p =.026) groups.
Health. Scores for the Health factor increased and then decreased over time for all four groups. The increases appear greater for the groups with lower immune functioning, but none of the pairwise differences in the estimated change in score over time was statistically significant. The difference between HIV- participants and the CD4+ Drop group approached significance (p =.043). Scores for the CD4+ Drop group at two time points and for the Low CD4+ group at all but one time point were above the 90th percentile, approaching clinical significance.
Cognition. Scores for the Cognition factor showed a slight increase and then decrease over time for all four groups. No pairwise differences between groups were significant.
Covariate Effects
The relationships between the covariates and outcome measures were complex
and will be presented here only briefly. Further information about covariate
effects is available from the first author. Age at baseline was significantly
associated with several of the Vineland and PBS measures and interacted with
HIV status or other covariates in several instances. Children who were older
at baseline showed higher Vineland Socialization but lower Communication
scores, and the latter effect was greater for the HIV- group. The lower
Communication scores in older participants may have been related to the focus
of the upper end of the scale on written language (see Discussion). Age at
baseline had a significant quadratic relationship to the Vineland Daily Living
and Composite scales, with scores decreasing and then increasing with greater
baseline age. Greater age at baseline was associated with lower scores on all
PBS factors, suggesting that caregivers report fewer emotional and behavioral
problems in general as their children become older. However, for four of the
factors (Conduct, Attention Deficits, Depression-Anxiety, and Deviation), this
effect was greater for the HIV+ groups. A history of head trauma was
associated with lower Vineland and higher PBS scores, or poorer outcome, in
general; however, this effect was significant only for the PBS Health factor
and approached significance for the PBS Depression-Anxiety and Deviation
factors.
As might be predicted, a history of academic problems was associated with lower scores on the Vineland Communication, Daily Living, and Socialization scales and with higher scores (i.e., greater problems) on several PBS factors, including Attention Deficits, Depression-Anxiety, Health, and Conduct. For the Vineland Communication and PBS Attention Deficits, Depression-Anxiety, and Health factors, history of academic problems interacted with time since baseline such that the negative effect of the covariate decreased over time, suggesting the possibility that its impact lessens as other factors become more influential. Consistent with this, a significant interaction for history of academic problems with HIV/CD4+ category was seen for the PBS Conduct and Depression-Anxiety factors; in both cases, the positive relationship between academic problems and the PBS scores was weakest for the Low CD4+ group.
Discussion
The results of this study provide only partial support for our hypothesis
that decreases in adaptive functioning and increases in behavioral and
emotional problems occur with greater immune compromise in children and
adolescents with hemophilia and HIV infection. Several areas of adaptive,
emotional, and behavioral functioning showed changes that were greater in
magnitude or differed in direction for the group of participants with the most
compromised immune functioning over time. The HIV- participants appeared to
maintain better adaptive functioning in all domains than those with HIV
infection and demonstrated less change in social-emotional functioning.
However, the greater changes shown by the HIV+ groups on the PBS were, in some
cases, in the direction of fewer reported problems, indicating improvements in
behavior, as discussed below.
Although the Low CD4+ group tended to do more poorly in all areas of
adaptive functioning, the most striking difference was the sharp decline on
the Vineland Communication scale after the second year of follow-up for this
group. In fact, this was the only area of the Vineland in which any mean
scores dropped below the average range. There are at least two possible
explanations for the dramatic decrease in Vineland Communication score in the
Low CD4+ group. First, language, particularly expressive language, is
especially vulnerable to the effects of HIV infection in children (e.g.,
Wolters, Brouwers, Moss, & Pizzo,
1997). Second, items at the higher end of the Communication scale,
generally administered for children over age 10, focus primarily on written
rather than spoken language. Thus, decreased school attendance and less energy
for schoolwork and pleasure reading, both of which could be likely occurrences
in the Low CD4+ group, may have contributed to a decline in these scores. The
low CD4+ group also showed less positive change than the other groups on the
Socialization and Daily Living scales. The results of the Vineland demonstrate
that adaptive functioning is an area vulnerable to changes with advancing HIV
disease and argue for the importance of including assessment of adaptive
functioning, particularly communication skills, in evaluations conducted with
HIV+ children and adolescents.
Behavior problems, as measured by the PBS, decreased over time for all four
groups on the Attention Deficit, Deviation, and Conduct factors. The HIV- and
High CD4+ groups showed significantly fewer problems over time. Participants
with greater immune compromise began the study with higher scores, or greater
problems, in these areas and showed steeper decreases in reported problems.
This may reflect fewer externalizing behaviors over time due to the effects of
illness and/or fatigue. As children or adolescents become less behaviorally
and socially active with disease progression, externalizing behaviors may
appear to decrease. Alternatively, problematic behaviors may be reported less
by care-givers as they become more focused on their child's declining health.
Although longitudinal trends in the Health and Depression-Anxiety factors did
not differ by group, the models indicated consistently more difficulties for
the Low CD4+ group on these factors at all time points, consistent with our
hypothesis. The greater problems seen for the Low CD4+ group on the
Depression-Anxiety factor indicate that caregivers view the children and
adolescents as experiencing distress most likely related to advancing HIV
disease. Nevertheless, levels of depression and anxiety as measured by the PBS
were within normal limits for the Low CD4+ group as well as for the other
participants. This study did not allow for comparisons of caregiver reports of
distress with self-reports by the child. Higher scores for the Low CD4+ group
may be related, at least in part, to the impact of increased levels of family
stress on the caregivers. It has been suggested that increased stress may also
contribute to disease progression in children with HIV infection
(Moss et al., 1998). Measures
of family stress were collected for a subset of the HGDS sample and will be
reported separately.
The reliance on caregiver report of adaptive and emotional functioning is a
potential limitation of this study. As noted above, caregivers' focus and
priorities may shift over the course of their child's illness and affect their
interpretation of the child's emotional state and behavior. In addition, the
children's perception of their behavior and emotional state may differ from
that of their caregivers. Bose et al.
(1994) compared child and
caregiver ratings for 36 families with HIV-positive children, the majority
infected via transfusions or clotting factor, and found that the caregivers
rated the children as having greater anxiety and poorer social competence than
the normative groups for the instruments used. In contrast, the children saw
themselves as less depressed and anxious than the healthy normative groups.
Similar comparisons in other populations have also found disagreements between
the ratings. For example, Radcliffe, Bennett, Kazak, Foley, and Phillips
(1996) found that the mothers
of children surviving brain tumors rated their children as having social and
communication difficulties even though the children described themselves as
comparable to their peers. These studies suggest that future studies of
adaptive and emotional functioning in children with HIV should include ratings
by the children as well as caregivers when possible.
Changes in some of the PBS factors might be related to therapeutic or scholastic interventions obtained by the participants during the course of the study. The effects of these interventions on the participants' emotional well-being or on the caregivers' perceptions of their children cannot be determined from this study. The Low CD4+ group tended to exhibit higher scores on the Depression-Anxiety scale throughout the study, despite being as likely or more likely than the other groups to receive supportive, educational, or mental health intervention.
The PBS findings build on an earlier observation by Mitchell et al.
(1997) from interview data
collected as part of the HGDS neurological examination. It was found that
HIV-positive participants with persistently low immune function were more
likely than those with high immune function to be identified by caregivers as
exhibiting changes in behavior. Although the two questions comprising behavior
change on the neurological examination were nonspecific, response to one of
the questions (Since his last visit, has the patient developed any permanent
changes in personality?) was significantly associated with all six general PBS
factors. The other question concerned whether the child had been sleeping or
resting more than usual during the previous 6 months. As might be predicted,
response to this question was significantly associated with the PBS Health
factor score.
The lack of group differences for the Cognition scale of the PBS appears
inconsistent with research reports of declining neuropsychological function
with HIV disease progression. The HGDS neuropsychological battery indicated
that greater immune compromise was associated with declines in
perceptual/performance skills, nonverbal memory, academic achievement, and
language (Loveland et al.,
2000). Thus, it is surprising that caregivers did not perceive
greater cognitive problems in children with more advanced HIV disease.
Attrition in the Low CD4+ group due to mortality may have reduced the
likelihood of observing group differences on the Cognition scale. It is also
important to point out the lower power for detecting differences between
groups in comparisons that involve the CD4+ Drop and Low CD4+ groups, owing to
the smaller sample sizes. However, the Cognition score is based in part on
caregiver views of school-related abilities and progress. As a result, the
low-average academic performance in all four groups may mask differences
between the groups. Furthermore, many of the children and adolescents in the
Low CD4+ group had very poor school attendance, which may make academic
problems less apparent to the caregivers. It is also possible that cognitive
changes such as those observed on formal neuropsychological testing are not
obvious to caregivers, particularly when a child has a history of poor
academic functioning. These results argue that, particularly as children are
living longer now with HIV disease, regular clinical assessments of
neuropsychological functioning are important and should not rely on caregiver
referrals.
Implications
This article reports the results of a large-scale longitudinal study of
adaptive, emotional, and behavioral functioning in a population of children
and adolescents with hemophilia, both HIV-infected and uninfected. In many
ways, the results of this study reflect the resilience of this population. The
majority of group means remained within the normal range throughout the study
for both HIV- and HIV+ participants. Nevertheless, significant changes within
the normal range provide evidence that advancing immune compromise is
associated with poorer adaptive functioning, particularly in the communication
domain, and with altered emotions and behavior in children and adolescents
infected postnatally with HIV.
The findings of this study have several implications for clinical practice and for future research. Regular assessment of adaptive, emotional, and behavioral functioning should be a standard component in ongoing evaluations of children and adolescents with HIV infection. These assessments should include both child and caregiver report measures. Changes in these areas of functioning, when observed, would suggest the need for therapeutic and educational services as well as for increased family support. Further research is needed to clarify the role of family functioning and other psychosocial risk factors in mediating the relationship between immune status and adaptive, emotional, and behavioral functioning. In addition, the potential of therapies targeted toward the central nervous system for preventing changes in these areas will be an important area of research as such therapies become available. Finally, little is known at this time about the effect of mental health and educational interventions on children's and their caregivers' adjustment to advancing HIV disease.
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The Hemophilia Growth and Development Study is funded by the following: National Institutes of Health, 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. The following individuals are the Center Directors, Study Coordinators, or Committee Chairs of the study: Childrens Hospital Los Angeles: E. Gomperts, MD, W.-Y. Wong, MD, F. Kaufman, MD, M. Nelson, MD, S. Pearson, RN; The 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; The National Institutes of Health, National Institute of Child Health and Human Development: A. Willoughby, MD, MPH; New England Research Institutes, Inc.: S. McKinlay, PhD; Rho, Inc.: S. Donfield, PhD; Baylor College of Medicine: C. Contant, Jr., PhD; University of Iowa Hospitals and Clinics: C. 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: M. 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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This work was supported by 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 are indebted to the children, adolescents, and caregivers who have volunteered to participate in this study and to the members of the Hemophilia Treatment Centers.
Received May 17, 1999; revision received October 15, 1999; accepted December 1, 1999
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