Journal of Pediatric Psychology, Vol. 25, No. 8, 2000, pp. 545–556
HIV-Associated Changes in Adaptive, Emotional, and Behavioral Functioning in Children and Adolescents With Hemophilia: Results From the Hemophilia Growth and Development Study Sharon Nichols,1 PhD, Elizabeth M. Mahoney,2 ScD, Patricia A. Sirois,3 PhD, Janice D. Bordeaux,4 PhD, James A. Stehbens,5 PhD, Katherine A. Loveland,6 PhD, Nancy Amodei,7 PhD, and the Hemophilia Growth and Development Study 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; and 7 University of Texas Health Science Center, San Antonio 1
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. The effect of human immunodeficiency virus (HIV) infection on a child’s or adolescent’s emotional 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:
[email protected]. 䉷 2000 Society of Pediatric Psychology
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
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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 dayto-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 viralinactivated, 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,
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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 HIVseropositive 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
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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,
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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.
Methods 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 ⱕ 15 years
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Procedures
Table I. Demographic Information by HIV Category HIV⫹ HIV⫺ n (at baseline)
126
High CD4 CD4 drop Low CD4 106 12.83
41
60
12.68
14.16
Age at baseline (years)
11.13
Deceased by year 4 (n)
0a
3
6
12.8
12.8
12.8
12.2
(%)b
25.6
33.3
42.5
32.2
Slow to speak (%)
11.2
3.8
7.5
6.8
Head trauma (%)
41.5
35.2
31.7
34.6
36
Caregiver education (years) Academic problems
a
b
Vital status at year 4 could not be determined for three of the HIV⫺ participants. Defined as having repeated a grade in school or placement in remedial special education classes, at the time of baseline.
of age and the lowest in adolescents ⱖ 18 years of age. Two hundred and seven of the participants were HIV-seropositive (HIV⫹), and 126 were HIVseronegative (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%). 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.
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 cochairs. 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 rat-
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ing 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; DepressionAnxiety, 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 4year 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⫹
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counts consistently ⬎200 cells/mm3; (3) CD4⫹ Drop group: HIV⫹ with the average of the first two counts ⱖ200 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 neurobehavioral 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 household), 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
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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 twoway 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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Figure 1 Predicted growth curves for Vineland Communication scale.
Figure 2 Predicted growth curves for PBS Conduct factor.
Results 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 through 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 fi-
nal model for an outcome, the average level of that covariate for the cohort as a whole was used in generating the predicted growth curves. 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
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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). Figure 3 Predicted growth curves for PBS Attention Deficits factor.
Figure 4 Predicted growth curves for PBS Deviation factor.
for the Low CD4⫹ group relative to the other three groups. Communication. Scores in the Communication domain increased with time since baseline for HIVparticipants 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
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 DepressionAnxiety 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
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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.
approached significance for the PBS DepressionAnxiety 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.
Covariate Effects
Discussion
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, DepressionAnxiety, 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
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
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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 caregivers 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
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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
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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 behav-
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ioral 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.
Appendix 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,
Social-Emotional Functioning in Pediatric HIV
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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Acknowledgments 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-HD4–3200), 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; revisions received October 15, 1999; accepted December 1, 1999
References Achenbach, T. M., & Edelbrock, C. (1983). Manual for the Child Behavior Checklist and Revised Child Behavior Profile. Burlington, VT: Thomas Achenbach. Agle, D., Gluck, H., & Pierce, G. F. (1987). The risk of AIDS: Psychologic impact on the hemophilic population. General Hospital Psychiatry, 9, 11–17. Akaike, H. (1973). Information theory and an extension of the maximum likelihood principle. In E. B. N. Petrov & F. Csaki (Eds.), 2nd International Symposium on Information Theory and Control (pp. 267–281). Budapest: Akademia Kiado. Bose, S., Moss, H. A., Brouwers, P., Pizzo, P., & Lorion, R. (1994). Psychologic adjustment of human immunodeficiency virus-infected school-age children. Developmental and Behavioral Pediatrics, 15, S26-S33. Brookmeyer, R., & Goedert, J. J. (1989). Censoring in an epidemic with an application to hemophiliaassociated AIDS. Biometrics, 45, 325–335. Brouwers, P., Tudor-Williams, G., DeCarli, C., Moss, H. A., Wolters, P. L., Civitello, L. A., & Pizzo, P. A. (1995). Relation between stage of disease and neurobehavioral measures in children with symptomatic HIV disease. AIDS, 9, 713–720.
Bussing, R., & Burket, R. C. (1993). Anxiety and intrafamilial stress in children with hemophilia after the HIV crisis. Journal of the American Academy of Child and Adolescent Psychiatry, 32, 562–567. Centers for Disease Control and Prevention. (1987). Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. Morbidity and Mortality Weekly Report, 36 (suppl 1). Colegrove, R. W., & Huntzinger, R. M. (1994). Academic, behavioral, and social adaptation of boys with hemophilia/HIV disease. Journal of Pediatric Psychology, 19, 457–473. Drotar, D. D., Agle, D. P., Eckl, C. L., & Thompson, P. A. (1995). Psychological response to HIV positivity in hemophilia. Pediatrics, 96, 1062–1069. Hilgartner, M. W., Donfield, S. M., Willoughby, A., Contant, C., Evatt, B., Gomperts, E., Hoots, K., Jason, J., Loveland, K., & Stehbens, J. A. (1993). Hemophilia Growth and Development Study: Design, methods, and entry data. American Journal of Pediatric Hematology/Oncology, 15, 208–218. Hooper, S. R., Whitt, J. K., Tennison, M., Burchinal, M., Gold, S., & Hall, C. (1993). Behavioral adaptation to
556
human immunodeficiency virus-seropositive status in children and adolescents with hemophilia. American Journal of Diseases of Children, 147, 541–545. Lindgren, S. D., & Koeppl, G. K. (1987). Assessing child behavior problems in a medical setting: Development of the Pediatric Behavior Scale. In R. Prinz (Ed.), Advances in behavioral assessment of children and families: Vol. 3 (pp. 57–90). Greenwich, CT: JAI. Loveland, K. A., Stehbens, J., Contant, C., Bordeaux, J. D., Sirois, P., Bell, T. S., & Hill, S. (1994). Hemophilia Growth and Development Study: Baseline neurodevelopmental findings. Journal of Pediatric Psychology, 19, 223–239. Loveland, K. A., Stehbens, J. A., Mahoney, E. M., Sirois, P. A., Nichols, S., Bordeaux, J. D., Watkins, J. M., Amodei, N., Hill, S. D., Donfield, S., & the Hemophilia Growth and Development Study. (2000). Declining immune function in children and adolescents with Hemophilia and HIV infection: Effects on neuropsychological performance. Journal of Pediatric Psychology, 25, 309–322. Mitchell, W., Lynn, H., Bale, J., Maeder, M., Donfield, S., Garg, B., Tilton, A., Willis, J., & Bohan, T. (1997). Longitudinal neurological follow-up of a group of HIV seropositive and HIV seronegative hemophiliacs: Results from the Hemophilia Growth and Development Study. Pediatrics, 100, 817–824. Moss, H., Bose, S., Wolters, P., & Brouwers, P. (1998). A preliminary study of factors associated with psychological adjustment and disease course in school-age children infected with the Human Immunodeficiency Virus. Developmental and Behavioral Pediatrics, 19, 18–25.
Nichols et al.
Price, R. W. (1996). Neurological complications of HIV infection. Lancet, 348, 445–52. Radcliffe, J., Bennett, D., Kazak, A. E., Foley, B., & Phillips, P. C. (1996). Adjustment in childhood brain tumor survival: Child, mother, and teacher report. Journal of Pediatric Psychology, 21, 529–539. Rubin, D. B. (1976). Inference and missing data. Biometrika, 63, 581–592. Selnes, O. A., Galai, N., Bacellar, H., Miller, E. N., Becker, J. T., Wesch, J., van Gorp, W., & McArthur, J. C. (1995). Cognitive performance after progression to AIDS: A longitudinal study from the Multicenter AIDS Cohort Study. Neurology, 45, 267–275. Sparrow, S. S., Balla, D. A., & Cicchetti, D. V. (1984). Vineland Adaptive Behavior Scales, Interview Edition. Circle Pines, MN: American Guidance Service. Stehbens, J. A., Loveland, K. A., Bordeaux, J. D., Contant, C., Schiller, M., Scott, A., Moylan, P. M., & Maeder, M. (1997). A collaborative model for research: Neurodevelopmental effects of HIV-1 in children and adolescents with hemophilia as an example. Children’s Health Care, 26, 115–135. Wolters, P. L., Brouwers, P., Moss, H. A., & Pizzo, P. A. (1994). Adaptive behavior of children with symptomatic HIV infection before and after zidovudine therapy. Journal of Pediatric Psychology, 19, 47–61. Wolters, P. L., Brouwers, P., Moss, H. A., & Pizzo, P. A. (1997). Receptive and expressive language function of children with symptomatic HIV infection and relationship with disease parameters: A longitudinal 24month follow-up study. AIDS, 11, 1135–1144.
