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Immune status in children The absolute CD4 cell count and the %CD4+ in healthy infants who are not infected with HIV are considerably higher than those observed in uninfected adults and slowly decline to adult values by the age of about six years. Age must therefore be taken into account as a variable in considering absolute CD4 counts or %CD4+ . Among children younger than five years of age, the absolute CD4 count tends to vary within an individual child more than the %CD4+. Currently, therefore, the measurement of the %CD4+ is thought to be more valuable in younger childreni . Absolute CD4 counts (and less so %CD4+) fluctuate within an individual and depend on intercurrent illness, physiological changes or test variability. Measuring the trend over two or three repeated measurements is therefore more informative than an individual value. Not all the equipment in use in resource-constrained settings can accurately estimate the %CD4+. The dedicated cytometers are designed to exclusively perform absolute CD4 measurements without the need for a haematology analyser and therefore do not provide %CD4+ii . Any classification of immune status has to consider age. The 1994 immunological classification of the United States CDC has previously been used [60]. WHO has proposed a modified immunological classification based on more recent analysis of the prognosis. Analysis of prognosis from 17 studies of children including 3941 children living with HIV from United States and European settings provide estimations of CD4 and age-related risk of progression to AIDS or death. A %CD4+ of 35 is associated with a 15% risk of progression to AIDS in the next 12 months among children aged three months and an 11% risk among those six months old. The revised WHO classification attempts to better reflect this increased risk in these younger children. Based on reanalysis of the data, the thresholds for severe immunodeficiency in children have been revised. For children in the WHO classification, age-related severe HIV-related immunodeficiency is defined as values at or below age-related CD4 thresholds below which children have a greater than 5% chance of disease progression to severe clinical events (AIDS) or death in the next 12 months. Further research is urgently required to assess the prognostic significance and to ascertain normal and disease-associated CD4 levels among African and Asian children. Note that, among children younger than one year, the immunological categories do not reflect the same level of risk at any given age; thus, a child six months old has a higher risk of progression for any given CD4 count than a child 11 months old. However, to facilitate the scaling up of access to antiretroviral therapy, WHO proposes this simplified harmonized immunological classification system for adults and children. The immune parameters and therefore classification improve with successful antiretroviral therapy . Immune parameters can be used to monitor the response to antiretroviral therapy, and it is hoped that the immunological classification will facilitate this. Immune status in adults The normal absolute CD4 count in adolescents and adults ranges from 500 to 1500 cells per mm3 of blood. In general, the CD4 (%CD4+ or absolute count) progressively decreases as HIV disease advances. As in children, individual counts may vary within an individual adult or adolescent and assessing the CD4 count over time is more useful. The CD4 count usually increases in response to effective combination antiretroviral therapy, although this may take many months. The proposed immunological classification outlines four bands of HIVrelated immunodeficiency: no significant immunodeficiency, mild immunodeficiency, advanced immunodeficiency and severe immunodeficiency. The likelihood of disease progression to AIDS or death without ART increases with increasing immunodeficiency (decreasing CD4), opportunistic infections and other HIV related conditions are increasingly likely with CD4 counts below 200 per mm3. Response to ART is affected by the immune stage at which it is started, people commencing ART with advanced immunodeficiency (CD4 >200–350 per mm3 ) appear to have better virological outcomes than those who commence with more severe immunodeficiency. Adults starting ART with CD4 <50 per mm3 have a much greater risk of death. Adults who commence ART with only mild immunodeficiency do not appear to obtain any additional benefits. Revised antiretroviral therapy recommendations reflect this.i Pregnancy does affect the CD4 count although the significance of these changes is not clearly understood, and for practical purposes the immunological classification remains the same. Clinical decision-making Regardless of age or clinical stage CD4 testing is very valuable and should be encouraged. It is useful to guide the decision on initiation of co-trimoxazole and when to start first-line ART or to identify treatment failure and the need to switch to a second-line regimen of ART. Measurement of CD4 can also be used to assess and monitor response to ART. Where clinical and immunological classifications are both available, immune status, reflected by CD4 (%CD4+ or absolute count) is usually more informative. This is reflected in the most up-todate WHO recommendations on ART for infants, children and adults.ii In younger children %CD4+ should be used, and from five years of age the absolute count is preferred. Severe HIV-related disease always requires ART irrespective of whether defined by clinical condition or immune status. Advanced HIV disease based on immune status requires considering ART, especially when disease is advanced as defined clinically. Starting antiretroviral therapy can usually be delayed if the immune status suggests that there is only mild or insignificant immunodeficiency (%CD4+ >30 among children younger than 12 months, >25 among children 12–35 months or >20 in children over 36 months, or CD4 count >350 per mm 3 in adults and older children), and the individual is asymptomatic or only has mild symptoms.