Régimen disciplinario interno a las PACL en el CPLPACL-R

Although the logio CD4^ cell count measurements were consistently lower for infected children, there was considerable overlap with measurements for uninfected children. For instance, o f the 2781 measurements on infected children, 1511 (54.3%) were above the running 5^ percentile for uninfected children (Figure 5.17). Overlap was especially pronounced at young ages (73.9% under one year) but decreased thereafter (56.8% at one to five years and 38.8% over five years). On the other hand, 73.5% o f measurements for uninfected children were below the 95^ percentile for infected children (Figure 5.18). Nearly 10 percent (8.3%) o f logio CD4^ cell count measurements in uninfected children fell into the CDC moderately (7.5%) or severely (0.8%) immunosuppressed categories, and 45.6% (26.4% and 19.2% respectively) o f those in infected children.

Figure 5.17: Observed values of logio CD4^ cell counts of infected children with 5th percentile for uninfected children

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o

o O) o

5th percentile uninfected children moderate immunosuppression se v e r e immunosuppression J ° 8 . ° _ «f*» 0»0*0 % Age (years) 10 "T “ 12 158

Figure 5.18: Observed values of logio CD4^ cell counts of uninfected children with 95th percentile for infected children

c 8 8

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if V

95th percentile infected children moderate immunosuppression se v e r e immunosuppression 10 T 12 Age (years)

An alternative way o f quantifying differences in levels for uninfected and infected children is

through the fitting o f a spline-based model for data on all children with terms for interactions

with infection status. This model included knots at one and three weeks, 3, six and 10

months, 3, six and 10 years and indicated substantial and significant differences in estimated

logio CD4^ cell counts between infected and uninfected children from birth onwards (Table

5.11). The largest absolute difference of 1296 x 10^ cells/1 was at 10 months, relating to the

measurements o f 993 uninfected and 145 infected children. This difference subsequently

decreased, to 509 x 10^ cells/1 at age 10 years, although the number of children tested at that

age was small, especially among uninfected children. Infected children who died consistently

had significantly lower logio CD4^ cell counts than infected children who survived (p<0.0001) (Appendix 5.2, Figure A5.5), and those tested at later ages were thus a selected population o f survivors. Nearly one third (14/47) o f children who died did so during the first year of life. Similar analyses revealed significantly lower values in infected children of CD4^ percent (p<0.001) and from three months onward o f CDS'*’ cell counts (p<0.001) and absolute lymphocyte counts (/?<0.001) throughout the 12 years o f follow-up.

Table 5.11: Predicted logio CD4^ cell count levels for uninfected and infected children

Age logic CD4^ cell counts (x 10^ cells/1) Absolute

difference /7-value* Uninfected children (absolute) n Infected children (absolute) n Intercept, age=0 3.253(1791) 90 3.191 (1552) 15 239 0.0152 1 week 3.453 (2836) 251 3.345 (2215) 30 621 0.0001 3 weeks 3.501 (3168) 351 3.406 (2545) 48 623 0.0003 3 months 3.447(2798) 801 3.331 (2142) 105 656 <0.0001 6 months 3.479 (3010) 1022 3.265 (1840) 138 1170 <0.0001 10 months 3.444 (2782) 993 3.172(1486) 145 1296 <0.0001 3 years 3.160 (1444) 460 2.788 (614) 112 830 <0.0001 6 years 3.007 (1016) 117 2.401 (252) 79 764 <0.0001 10 years 2.906(805) 18 2.472 (296) 35 509 <0.0001 * from M ests 160

Key points: Patterns of immunological markers in uninfected children

• Levels of CD4^ cell counts peaked twice early and did not approach adult values until after age 6 years.

• Estimated patterns for CD8^ and absolute lymphocytes were similar to those of CD4^ cell counts.

• The early double peaks in predicted C D 4 \ CD8^ cell counts and absolute lymphocytes for uninfected children highlights the complex and dynamic nature of a developing immune system.

• CD4^ cell counts, absolute lymphocytes and CD4^ percentage values were higher for girls.

• Levels of all four markers were higher in white children.

• Gender and race differences were not explained by a general increase in absolute lymphocytes.

• There was a significant association of maternal CD4’*’ cell count with child CD4^ cell count

Table 5.12: Sum m ary of gender and race effects for lymphocyte patterns in uninfected children Factor Level or P attern logio CD4^ cell count logic CDS^ cell count logic absolute lymphocyte CD4+ percentage G ender level girls higher no girls higher girls higher

pattern yes yes yes yes

Race level white higher white higher white higher white higher

pattern borderline yes no no

Key points: Patterns of immunological markers in infected children

• CD4^ values peaked in children at seven weeks o f age, below the peak seen in uninfected children.

• CD8^ cell counts were higher than CD4^ cell counts after eight months o f age. • Gender differences in C D 4 \ CD8^ cell counts and absolute lymphocytes levels in

infected children were in an opposite direction to those seen in uninfected children, with higher levels in boys.

• Gender differences for CD4^ percentage were not consistent for infected children. • Levels for all four markers were generally higher for white than black children,

though there was evidence of a switch in later childhood.

Table 5.13: Sum m ary of gender and race effects for lymphocyte patterns in infected children Factor Level or P attern logio CD4^ cell count logio CD8^ cell count logio absolute lymphocyte C D f percentage Gender level boys higher boys higher boys higher Not consistent

pattern yes yes yes yes

Race level white higher white higher until 3 years

borderline white higher after 1 year

pattern yes yes borderline yes

Key points: Comparison of patterns of immunological markers in uninfected and infected children

• Levels were substantially lower in infected children and patterns were distinctly different.

• There was considerable overlap between measurements for uninfected and infected children with more than half the measurements for infected children exceeding the 5^ percentile for uninfected children.

• However, estimated CD4^ cell counts differed by as much as almost 1300 x 10^ cells/1 at 10 months of age.

• Significant differences existed by race, which, when compared with gender differences, were more consistent by infection status with generally higher levels for white than black children, though there was evidence of a switch in later childhood.

• Race differences were independent of gender.

Chapter 6 Results: Early-life determinants of clinical disease progression in