Early immunological predictors of neurodevelopmental outcomes in HIV-infected children

Abstract

Background: A previous analysis of children infected with human immunodeficiency virus (HIV) in the Women and Infants Transmission Study showed a strong correlation between low activated CD8(+) T lymphocytes in the first 2 months of life and good immunological prognosis. We sought to extend these observations to neurodevelopmental prognosis.

Methods: Ninety-eight HIV-infected children born before 1994 with flow cytometric data from the first 2 months of life and adequate neurodevelopmental testing through age 30 months were studied. Children were divided into those with low (<or=5% CD8(+)HLA-DR(+) cells or <or=25% CD8(+)CD38(+) cells) or high (>5% CD8(+)HLA-DR(+) cells or >25% CD8(+)CD38(+) cells) immune activation at 1 and/or 2 months of age. Analysis was performed using survival analysis, Cox's proportional hazard regression, and longitudinal regression models.

Results: Absence of immune activation, measured as <or=5% CD8(+)HLA-DR(+) cells, was strongly associated with better performance on the psychomotor developmental index of the Bayley scales of infant development through the third year of life. This association persisted after adjustment for CD4 cell count, viral load, and progression to acquired immunodeficiency syndrome (P= .005). An association with the mental development index was also present (P= .048). Significant association between neurodevelopmental outcomes and <or=25% CD8(+)CD38(+) cells was not seen.

Conclusions: In this prospective cohort study of HIV-infected children, there was a significant favorable association of low immune activation in peripheral T cells at age 1 or 2 months, measured by a low percentage of CD8(+)HLA-DR(+) cells, with subsequent psychomotor and mental development. This association was independent of other indices of severity and progression of HIV infection.

Figure 1

Box plots showing range (whiskers), 25th–75th percentiles (shaded box), median (horizontal line), and outliers (open circles and asterisk) of psychomotor developmental index at ages 4, 12, 18, 24, and 30 months, in relation to immune activation as measured by the percentage of CD8+HLA-DR+ cells. The number of children with tests at each age (n) is shown below each plot.

Figure 2

Box plots showing range (whiskers), 25th–75th percentiles (shaded box), median (horizontal line), and outliers (open circles and asterisk) of mental developmental index at ages 4, 12, 18, 24, and 30 months, in relation to immune activation as measured by the percentage of CD8+HLADR+ cells. The number of children with tests at each age (n) is shown below each plot.

Figure 3

Relationship between immune activation—as measured by CD8+HLA-DR+ cell percentage of>15% or ⩽5% at age 1–2 months (A) or as measured by CD8+CD38+ cell percentage of >25% or ⩽25% at age 1–2 months (B)—and Kaplan-Meier estimate of time to below-normal score (11 SD below the mean) on the psychomotor developmental index of the Bayley scales of infant development. Solid lines, high immune activation; dotted lines, low immune activation.

Figure 4

Relationship between immune activation—as measured by CD8+HLA-DR+ cell percentage of >5% or ⩽5% at age 1–2 months (A) or as measured by CD8+CD38+ cell percentage of 125% or 25% at age 1–2 months (B)—and Kaplan-Meier estimate of time to below-normal score (>1 SD below the mean) on the mental developmental index of the Bayley scales of infant development. Solid lines, high immune activation; dotted lines, low immune activation.

Table 1

Estimates of the expected slope of scores on Bayley scales of infant development, according to early markers of immune activation, based on longitudinal regression models.