ELECTRONIC ARTICLE |



* National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia
Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts
Department of Pediatrics, University of Medicine and Dentistry of New Jersey, Newark, New Jersey
|| Departments of Infectious Diseases and Child and Adolescent Psychiatry, Children's Memorial Hospital, Chicago, Illinois
¶ Community Constituency Group, Conroe, Texas
# Department of Pediatric Infectious Disease, State University of New York, Health Science Center, Stony Brook, New York
| ABSTRACT |
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Methods. The Pediatric Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Group (PACTG) 219C is a prospective cohort study designed to examine long-term outcomes among HIV-infected children and HIV-uninfected infants born to HIV-infected women. Children with HIV infection who have enrolled in PACTG 219C are examined quarterly, with collection of clinical and laboratory data. Hospitalizations and diagnoses for all participants between September 2000 (when enrollment into PACTG 219C was started) and December 2002 were reviewed.
Results. Among 1808 HIV-infected participants who were <15 years of age at the last visit date, 25 children had been hospitalized for psychiatric manifestations, 8 before enrollment into PACTG 219C. Seventeen children were hospitalized during 2757 person-years of follow-up monitoring after entry into PACTG 219C, which represents an incidence of 6.17 cases per 1000 person-years (95% confidence interval: 3.599.87 cases per 1000 person-years). This was significantly higher than the incidence of 1.70 cases per 1000 person-years (95% confidence interval: 1.671.72 cases per 1000 person-years) in the general pediatric population <15 years of age, as reported in the 2000 National Hospital Discharge Survey, yielding a relative rate of 3.62 (95% confidence interval: 2.115.80). A total of 32 HIV-infected children, regardless of age, were hospitalized because of psychiatric illnesses. The majority of patients were admitted because of depression (n = 16) or behavioral disorders (n = 8). Fifteen (47%) underwent multiple psychiatric hospitalizations. The median age at the first psychiatric hospitalization was 11 years (range: 417 years); all patients had been perinatally infected. Knowledge of HIV seropositivity status and having experienced a significant life event were both significantly associated with an increased risk of psychiatric hospitalization (hazard ratios of 6.13 and 3.04, respectively). No psychiatric hospitalizations were observed among the 1021 HIV-uninfected members of the cohort.
Conclusions. Children with HIV/AIDS are at increased risk for psychiatric hospitalizations during childhood and early adolescence, compared with the general pediatric population. Knowledge of HIV seropositivity status and recent significant life events were significantly associated with increased risks of admission in this population.
Key Words: HIV/AIDS pediatrics psychiatric hospitalization psychologic distress disclosure proportional hazards regression
Abbreviations: HIV, human immunodeficiency virus AIDS, acquired immunodeficiency syndrome PACTG, Pediatric AIDS Clinical Trials Group NHDS, National Hospital Discharge Survey WITS, Women and Infants Transmission Study
As the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) epidemic enters its third decade, advances in treatment, most notably combination therapy with a protease inhibitor and improved prophylaxis, have transformed the disease from a rapidly fatal infection into a chronic illness, greatly extending the life expectancy of infected individuals.1 As children live longer with chronic HIV infection, however, they may be at greater risk of increased incidence and severity of complications, including psychiatric illnesses.
Psychologic manifestations among children with life-limiting or chronic illnesses have been reported.27 Conflicting findings suggest a multifactorial relationship defined by the disease, the degree of social support, and the quality of and access to medical care. Bennett8 reviewed 60 studies of depressive symptoms among children and adolescents with chronic medical problems and concluded that chronically ill children were at slightly elevated risk for depressive symptoms but not clinical depression. He reported that the risk may depend on the disorder, ie, children with asthma, recurrent abdominal pain, or sickle cell anemia are possibly at greater risk than children with other chronic disorders such as cancer, cystic fibrosis, or diabetes mellitus.8 A recent case-control study found no significant differences in depression, anxiety, or loneliness ratings among 76 children with cancer, compared with school-age peer control subjects.9
Children with HIV infection have additional risk factors for mental illness, including poverty, a disrupted home life, a family history of mental illness, psychiatric disorders, and/or substance abuse, and inadequate social support. Other possible risk factors that are more specific for HIV infection include forced disclosure of HIV status to others, fear of progression to AIDS, and body image concerns resulting from delayed development, chronic dermatologic conditions, or lipodystrophy/lipoatrophy.10 Psychologic problems among children and youths with HIV infection have been documented.1118 In a convenience sample of 34 HIV-positive adolescents, Pao et al19 reported a prevalence rate of 44% for ongoing depressive disorders and a 68% lifetime risk of an affective disorder. The study also reported phobias and anxiety disorders, as well as a 59% prevalence rate of substance abuse.
Recent data from the Women and Infants Transmission Study (WITS) indicated high rates of emotional and behavioral problems among HIV-infected children between the ages of 3 and 7 years. The association ceased to be significant, however, in multivariate analyses comparing the HIV-infected children with HIV-exposed, uninfected, control subjects, which led the authors to conclude that the relationship between these disorders and HIV may be attributable to psychosocial factors, as opposed to the disease itself.20
In the general pediatric population, stressful life events often precede depression or suicide attempts.21,22 In a longitudinal study of 24 HIV-infected children assessed at baseline and 2 years later, Moss et al23 reported an association between negative life events and adverse psychologic and behavioral outcomes. In the adult HIV literature, mental disorders (specifically acute stress reactions) are reported to be most common immediately after notification of HIV seropositivity, occurring for up to 90% of subjects.24
Lester et al25 examined factors related to emotional distress among 51 children with perinatal HIV infection. In cross-sectional univariate analyses, HIV disclosure and major life events were associated with increased parent-rated anxiety. However, after adjustment for age, major life events, and medication dose, HIV disclosure ceased to be significant. The authors acknowledged that the study was limited by the small sample size.
The incidence of psychiatric hospitalization in the pediatric HIV-infected population has not been investigated extensively. Hein et al12 reported increased numbers of psychiatric hospitalizations among 72 HIV-infected adolescents, compared with 1142 uninfected control subjects receiving care in an urban adolescent clinical care unit. The purpose of this analysis of the Pediatric AIDS Clinical Trials Group (PACTG) 219C database was to determine the incidence of psychiatric hospitalizations among members of the cohort with HIV infection and to examine predictors of first psychiatric hospitalization.
| METHODS |
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Eligible subjects for PACTG 219C include all perinatally HIV-exposed (infected, undetermined status, or uninfected) infants, children, and adolescents and children with postperinatally acquired HIV infection being monitored at a PACTG site. Infected children enrolled in PACTG 219C are examined quarterly, with routine clinical and laboratory evaluations. The PACTG 219C database was reviewed for psychiatric hospitalizations among perinatally HIV-infected and perinatally HIV-exposed, uninfected participants (children and adolescents) between September 2000 (when enrollment in PACTG 219C was initiated) and December 2002. An incident case was defined as a psychiatric hospitalization after the individual's PACTG 219C study enrollment date. A prevalent case was defined as a psychiatric hospitalization before the individual's study enrollment date. Prevalent cases were excluded from the incidence analyses to avoid ascertainment bias.
Knowledge of HIV seropositivity status and significant life events are assessed quarterly in PACTG 219C with the General Health Assessment for Children.26 This age-specific questionnaire, which is modular in design, documents whether the individual has been informed of his or her HIV seropositivity status and includes some or all of the following domains: general health perceptions, physical resilience, physical function, psychologic function, social and role function, health care utilization, and disease-related symptoms. The General Health Assessment for Children has been demonstrated to have good psychometric properties.27 A significant life event was defined as a positive response regarding any of the following 18 points on the General Health Assessment for Children: parent lost job, family member left home, loss of housing or had to move, loss of entitlement, loss of health insurance, family member hospitalized, family member very sick, change of caregiver, separation of parents, divorce of parents, jail sentence of parent, marriage of parent, birth of a sibling, mother starting to work, beginning school or moving to a new school, change in financial status of parents, loss of a close friend (to child), or death in the family.
The incidence of psychiatric hospitalizations in the general pediatric population was obtained from the National Hospital Discharge Survey (NHDS).28 The NHDS is an annual, national, probability survey detailing characteristics of inpatients discharged from nonfederal, short-stay hospitals in the United States. The NHDS collects data from a sample of
270 000 inpatient records acquired from a national sample of
500 hospitals. Only hospitals with an average length of stay of <30 days for all patients, general hospitals, and children's general hospitals are included in the survey.
Statistical Methods
The relative risks and 95% exact confidence intervals were calculated using maximum likelihood estimation of the Poisson rate parameters of the incidence of psychiatric hospitalizations among HIV-infected PACTG 219C participants <15 years of age. This age restriction was necessary to enable comparisons with the incidence for the general pediatric population reported in the 2000 NHDS. Observation times were calculated in person-years for both populations. The 2 rates then were compared for homogeneity.
Because age-specific rates of hospitalization are not available in the NHDS, indirect age standardization was used to allow for the possibility that the age distribution for children in the PACTG 219C cohort was different from that observed in the general pediatric population. This standardization involved applying the rate of hospitalization observed in PACTG 219C for infected children in each year of age to the number of children in the United States having that age, to provide a predicted number of hospitalizations in the pediatric population in the United States. This then was compared with the number in the NHDS to yield an age-adjusted relative risk. It was not possible to estimate the standard error of this relative risk, however, because of the small numbers (sometimes zero) of hospitalizations for some ages in PACTG 219C.
Cox proportional hazards regression techniques29 were used to examine predictors of first psychiatric hospitalization for all incident cases regardless of age. Demographic and clinical variables including age, gender, race/ethnicity (non-Hispanic white, non-Hispanic black, or Hispanic), caregiver status (biologic parent versus other), time-varying values for knowledge of HIV status, recent significant life events, CD4 percentage, HIV-1 RNA viral load (<400 copies per mL vs
400 copies per mL), and antiretroviral medications (specifically nonnucleoside reverse transcriptase inhibitors and protease inhibitors) were examined with respect to their associations with first psychiatric hospitalization.
| RESULTS |
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Proportional hazards univariate regression models revealed that knowledge of HIV seropositivity status and significant life events were associated with increased risks of psychiatric hospitalization (Table 2). In a multivariate analysis that included these 2 variables, participants who were aware of their HIV seropositivity status were 6 times more likely to be hospitalized because of psychiatric illnesses, compared with participants who were unaware of their HIV status (hazard ratio: 6.13). Participants who reported a significant life event were 3 times more likely to be hospitalized because of psychiatric illnesses, compared with participants who did not report such an event (hazard ratio: 3.04). Race/ethnicity, gender, age, caregiver status, immunologic and virologic markers, and nonnucleoside reverse transcriptase inhibitor and protease inhibitor antiretroviral medications were not significantly associated with first psychiatric hospitalizations.
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3 times. At the first psychiatric hospitalization, the median age was 11 years (range: 417 years), 20 patients were male (63%), 28 patients (88%) were aware of their HIV seropositivity status, 14 patients (44%) had a previous psychiatric diagnosis, and 10 patients (31%) had been treated with a psychotropic medication previously. All patients had been exposed to a nucleoside reverse transcriptase inhibitor before their first psychiatric hospitalizations, 26 patients (81%) had been exposed to a protease inhibitor, and 15 patients (47%) had been exposed to a nonnucleoside reverse transcriptase inhibitor. The median length of stay for all psychiatric hospitalizations was 7 days (range: 1252 days). During the 2757 person-years of observation, 276 person-days of psychiatric hospitalization occurred. This is equivalent to 100 person-days of hospitalization per 1000 person-years of follow-up monitoring.
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| DISCUSSION |
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In a multivariate analysis, individuals aware of their HIV seropositivity status were 6 times more likely to be hospitalized for psychiatric illness compared with those unaware of their HIV status. Also, those reporting a significant life event were 3 times more likely to be hospitalized for psychiatric illness compared with those not reporting such an event. Because of insufficient statistical power, we were unable to examine associations between psychiatric hospitalization and the 18 individual significant life events. It is possible that that there are varying degrees of predictability among these events. Clinicians should be aware that these occurrences might precipitate a psychiatric crisis, particularly in the context of a preexisting psychiatric disorder or mental health issue.
Data from the WITS found no significant difference in emotional and behavioral problems in HIV-infected children compared to HIV-exposed, uninfected controls and concluded that the relationship between these disorders and HIV may be attributed to psychosocial factors rather than HIV. However, the WITS population was restricted to children <7 years old. In the PACTG 219C sample, the marginally significant age effect in the unadjusted analysis disappears when age is included in a multivariate analysis that also includes knowledge of HIV seropositivity status. A likely explanation is that the older a child is, the more likely they are to know their HIV seropositivity status. This may explain the discrepancy in the findings between the PACTG 219C sample and the WITS population. It is important to note, however, that there were significant differences in design between the 2 populations with PACTG 219C focusing on psychiatric hospitalizations as opposed to emotional/behavioral problems.
Hein et al12 reported increased psychiatric hospitalization rates among HIV-infected adolescents, compared with uninfected control subjects. The majority of infected participants in the sample had acquired HIV infection through high-risk behaviors, as opposed to perinatal exposure. It is possible that psychiatric manifestations may differ for these 2 populations, because the acute and chronic effects of HIV infection during neurodevelopment may predispose children with perinatally acquired HIV infection to specific mental illnesses. The association between HIV acquisition and psychiatric illness should be investigated more thoroughly.
Depression and behavioral disorders were the 2 most common reasons for psychiatric hospitalizations for the PACTG 219C cohort. The prevalence of mood disorders in the general pediatric population (specifically major depressive disorder, dysthymia, and cyclothymia or bipolar disorder) has been estimated at 2% for prepubertal children and 5% for adolescents.30 Before puberty, similar rates of depression are observed for male and female subjects. However, adolescent and adult female subjects are more than twice as likely as male subjects to be affected.31,32 With respect to behavioral disorders, prevalence estimates for attention-deficit/hyperactivity disorder vary from 3%5% to 8%17% for community samples to 30%50% for child psychiatric outpatients and 40%70% for child psychiatric inpatients. The rates for male and female subjects differ by a 4:1 ratio.31,32 The rates of oppositional defiant disorder are higher among prepubescent male subjects. However, the rates for male and female subjects are equal after puberty.33
Evidence suggests that affective and behavioral disorders may be precursors to more severe psychopathologic conditions, eg, bipolar disorder and suicide. Weissman et al34 reported that, in a 10- to 15-year follow-up study of adolescents diagnosed with major depression, 7% committed suicide some time later. The depressed adolescents were also 5 times more likely to have attempted suicide in the follow-up period, compared with age-adjusted control subjects without depression.34 Controlled studies of suicide suggest similar risk factors for both genders.35 Shaffer et al35 reported a 12-fold increased risk of suicide among adolescent female and male subjects with a diagnosis of major depressive disorder. Disruptive behavior disorders increased the suicide rate for male subjects 2-fold.
In 2000, suicide was the third leading cause of death for subjects 10 to 24 years of age.36 Between 1980 and 1997, the rate of suicide among persons 15 to 19 years of age increased 11%. Among non-Hispanic, black, male subjects, the rate increased 105% during this period. Among persons 10 to 14 years of age, the rate increased 109%.37 Therefore, the higher rate of depression found for our cohort of children and adolescents infected with HIV suggests that clinicians should be alert for potential increased risks of suicide in this population.
Of the 32 children with psychiatric hospitalizations in the PACTG 219C cohort, 15 (47%) experienced multiple admissions. The phenomenon of multiple hospitalizations has been observed in the general population. Studies found that 20% to 40% of children with depression experienced relapse within 2 years and 70% experienced relapse by adulthood.3840
Disease status, as measured by CD4 percentage and viral load, was not significantly associated with first psychiatric hospitalizations. Zorrilla et al41 reviewed 19 studies examining the relationship between depressive symptoms and HIV progression and failed to find a relationship except for an increase in the reports of disease symptoms. The HIV-infected children in PACTG 219C experienced substantial exposure to all 3 classes of antiretroviral drugs before their first psychiatric hospitalizations. All had been exposed to a nucleoside reverse transcriptase inhibitor, 81% had been exposed to a protease inhibitor, and 47% had been exposed to a nonnucleoside reverse transcriptase inhibitor. These percentages are comparable with the percentages of patients in the overall cohort who have received each class of drug. For protease inhibitors and nonnucleoside reverse transcriptase inhibitors, we found no significant association between use of the drugs and the risk of psychiatric hospitalization. Because all subjects had received a nucleoside reverse transcriptase inhibitor, it was not possible to evaluate an association with that class of drugs.
The median time spent in the hospital for the PACTG 219C participants was 7 days. This was less than the mean length of stay in the general pediatric population, which averaged 12.4 days for mental disorders. There may be multiple complex reasons for this observation of a shorter length of stay for psychiatric admissions among children with HIV infection. Children with HIV may be released earlier because of the comprehensive care programs provided at PACTG sites and support systems developed by the pediatric care team, which allow early discharge to home care. Alternatively, complications of the HIV illness and the cost of treatment may discourage lengthy hospitalizations. Whether early release contributes to the recidivism rate of nearly 50% is unclear. Associations between the length of stay and rehospitalization should be investigated more thoroughly.
As with any observational study, there is a degree of confounding by severity, insofar as the children with the most severe mental disorders may not be able to meet the demands of the study, ie, neuropsychologic testing and other lengthy clinical assessments, and thus may not be enrolled in PACTG 219C or, if enrolled, may be lost to follow-up monitoring. These reported rates are specific to the PACTG 219C cohort and may underestimate rates in the broader HIV-infected pediatric population.
As these children live longer with chronic HIV infection, the incidences of psychiatric hospitalizations and major psychiatric illness may increase. Screening for warning signs of psychiatric illness should be provided within the context of comprehensive primary care, particularly at important points of transition in a child's life. Parent- and self-report instruments can be used to identify and monitor emotional and behavioral problems. Referrals for mental health services should be provided when psychiatric issues become apparent, and risk factors for treatment failure, such as an unsafe family/home environment and a family history of mental illness, should be recognized. Additional research is needed to adequately characterize the complex etiologic factors for severe psychiatric symptoms associated with HIV infection among children and adolescents, so that the quality of life matches the marked gains observed in survival times.
| ACKNOWLEDGMENTS |
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We recognize the tremendous effort of the children and families to participate in this late-outcomes study, and we hope that our observations help improve their quality of life. The following institutions and individuals participated in PACTG Protocol 219C. University of Medicine and Dentistry of New Jersey University Hospital: P. Palumbo and M.J. Hoyt; St. Joseph's Hospital and Medical Center: N. Hutchcon and A. Townley; Cooper Hospital-University Medical Center: A. Feingold and S. Burrows-Clark; University of Rochester: F. Gigliotti and B. Murante; Columbus Children's Hospital: M. Brady and J. Hunkler; Children's Hospital of Boston: K. McIntosh and K. Bertelsen; Boston Medical Center: S. Pelton and A. Regan; University of North Carolina: T. Belhorn and E. Pitkin; University of California, Los Angeles: Y. Bryson and M. Dillon; Children's Hospital of Los Angeles: J. Church and C. Salata; Long Beach Memorial: A. Deveikis and L. Melton; Harbor-UCLA Medical Center: M. Keller and J. Hayes; Johns Hopkins University: N. Hutton and S. Marvin; University of Maryland: P. Vink and K. Fore; Baylor College of Medicine/Texas Children's Hospital: W. Shearer and K. Owl; Chicago Children's Memorial Hospital: R.Yogev and D. Fonken-Cloutier; Cook County Hospital: K. Boyer and E. Gliwa; University of Chicago Children's Hospital: J. Englund and P. Lofton; Women and Children's HIV Program: D. Johnson and B. Wolfe; Columbia Presbyterian Medical Center: A. Gershon and M. Donahue; Incarnation Children's Center: A. Gershon and P. Miller; Cornell University-New York Presbyterian Hospital: A. Gershon and A. Monroe; University of Miami: G. Scott and P. Bryan; Jackson Memorial Hospital: M.J. O'Sullivan and P. Bryan; New York University-Bellevue Hospital: W. Borkowsky and N. Deygoo; University of California, San Francisco-Moffitt Hospital: D. Wara and D. Trevithick; San Francisco General Hospital: D. Wara and M. Shannon; Children's Hospital of Oakland: A. Petru and T. Courville; Phoenix Children's Hospital: J. Platt and L. Clarke-Steffen; University of California, San Diego: S. Spector and M. Caffery; Duke University: R. McKinney, Jr, and J. Swetnam; St. Jude's Children's Research Hospital: P. Flynn and J. Utech; University of Puerto Rico: I. Febo Rodriguez and S. Nieves; Children's Hospital of Philadelphia: S. Starr and C. Vincent; Children's Hospital of Seattle: L. Frenkel and K. Mohan; Bronx Municipal Hospital/Jacobi Medical Center: A. Wiznia and W. Biernick; Children's Hospital of Washington, DC: H. Spiegel and J. Ziegler; Tulane University: R. Van Dyke and M. Cowie; University of Massachusetts: K. Luzuriaga and D. Christian; Baystate Medical Center: B. Stechenberg and M. Toye; University of Connecticut/Connecticut Children's Medical Center: J. Salazar and G. Karas; Schneider Children's Hospital: V. Bonagura and C. Colter; Metropolitan Hospital Center: M. Bamji and K. Novita; Harlem Hospital: E. Abrams and D. Calo; University of Cincinnati: J. Mrus and N. Boosveld; State University of New York-Brooklyn: E. Handelsman and D. Swindell; North Shore University Hospital: S. Pahwa and L. Rodriquez; St. Christopher's Hospital: M. Bagarazzi and R. Buie; Oregon Health Sciences University: P. Lewis and R. Croteau; Bronx Lebanon Hospital Center: S. Bakshi and C. Nubel; St. Luke's/Roosevelt Hospital Center: S. Arpadi and R. Warford; Cornell University: R. Johan-Liang and K. O'Keefe; University of Illinois: K. Rich and J. Camacho; Emory University Hospital: S. Nesheim and R. Dennis; San Juan City Hospital: E. Jimenez and M. Thurin; Children's Hospital of the King's Daughters: T. Rubio and D. Sandifer; University of Medicine and Dentistry of New Jersey-Robert Wood Johnson: S. Gaur and L. Cerrachio; Ramon Ruiz Arnau University Hospital: W. Figueroa and E. Reyes; Medical College of Georgia: W. Foshee and S. Cobb; University of South Alabama: M. Mancao and J. Bebawy; The Medical Center: R. Stauffer and D. Barnes; Medical University of South Carolina: G. Johnson and A. Cope; Yale University School of Medicine: W. Andiman and D. Schroeder; State University of New York Health Science Center at Syracuse: C. Cunningham and K. Contello; State University of New York-Stony Brook: S. Nachman and M. Davi; Children's Hospital of Michigan: E. Moore and C. Cromer; Children's Hospital at Albany Medical Center: N. Wade and M. Adams; Children's Hospital of Dallas: J. Squires and D. Perry; Howard University Hospital: S. Rana and P. Yu; University of Alabama at Birmingham: R. Pass and T. Byars; Los Angeles County Medical Center/University of Southern California: A. Kovacs and E. Operskalski; Montefiore Medical Center/Albert Einstein College of Medicine: A. Rubinstein and G. Krienik; University of Florida Health Sciences Center: M. Rathore and M. Eagle; University of Mississippi: H. Gay and S. Sadler; Medical College of Virginia: S. Lavoie and T. Smith; Denver Children's Hospital: E. McFarland and C. Salbenblatt; North Broward Hospital District: A. Puga and D. Cruz; University of Florida-Gainesville: J. Sleasman and C. Delaney; Palm Beach County Health Department: G. Stiebel-Chin and P. Vann; Vanderbilt University Medical Center: G. Wilson and P. Bender; Earl K. Long Early Intervention Clinic: R. VanDyke and M. Cowie; Sacred Heart Children's Hospital/Children's Medical Services of Florida; St. Louis Children's Hospital: G. Storch and L. Stiffler; Robert Wood Johnson AIDS Program: S. Gaur and L. Cerrachio; and University of South Florida: P. Emmanuel and C. Graisbery.
| FOOTNOTES |
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Address correspondence to Sharon Nachman, MD, Department of Pediatric Infectious Disease, State University of New York, Health Science Center, T11-060, Stony Brook, NY 11794-8111. E-mail: sharon.nachman{at}stonybrook.edu
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