Tuberculosis in HIV-infected South African children with complicated severe acute malnutrition.

SETTING: Academic tertiary referral hospital in Durban, South Africa. OBJECTIVE: To describe the incidence and diagnostic challenges of tuberculosis (TB) in human immunodeficiency virus (HIV) infected children with severe acute malnutrition (SAM). DESIGN: Post-hoc analysis of a randomised controlled trial that enrolled antiretroviral therapy naïve, HIV-infected children with SAM. Trial records and hospital laboratory results were explored for clinical diagnoses and bacteriologically confirmed cases of TB. Negative binomial regression was used to explore associations with confirmed cases of TB, excluding cases where the clinical diagnosis was not supported by microbiological confirmation. RESULTS: Of 82 children enrolled in the study, 21 (25.6%) were diagnosed with TB, with bacteriological confirmation in 8 cases. Sputum sampling (as opposed to gastric washings) was associated with an increased risk of subsequent diagnosis of TB (adjusted relative risk [aRR] 1.134, 95%CI 1.02-1.26). Culture-proven bacterial infection during admission was associated with a reduced risk of TB (aRR 0.856, 95%CI 0.748-0.979), which may reflect false-negative microbiological tests secondary to empiric broad-spectrum antibiotics. CONCLUSION: TB is common in HIV-infected children with SAM. While microbiological confirmation of the diagnosis is feasible, empiric treatment remains common, possibly influenced by suboptimal testing and false-negative TB diagnostics. Rigorous microbiological TB investigation should be integrated into the programmatic management of HIV and SAM.

Lymphocyte subset changes between 3 and 15 months of age in infants born to HIV-seropositive women in South Africa.

The evolution of T-lymphocyte subsets during infancy in perinatally HIV-infected African babies has not been previously described. In a hospital-based cohort study, T-lymphocyte subset changes were investigated in 72 South African black children born to HIV seropositive mothers. Sixteen (22.2%; children were classified as infected and 56 (77.8%) as uninfected by 18 months of age. Four (25%) of the infected infants died before the age of 9 months from HIV-related disease. The CD4 and CD8 T-lymphocyte subsets, expressed in absolute numbers, as percentages, percentiles or as ratios, were clear indicators of HIV infection at all ages between 3 and 15 months. The most marked changes were a decreased percentage of CD4 cells and an increase in percentage of CD8 cells in the infected group. In the 4 infected infants who died, CD8 count and CD4:CD8 ratio clearly predicted poor clinical outcome at 3 months. Taken together, both CD4:CD8 ratio and CD4 percentage are reliable markers of HIV infection in an African paediatric population; however, a raised CD8 lymphocyte count rather than a CD4 count is a more specific prognostic marker of disease progression in HIV infected children.

The relationship between maternal-infant antibody levels and vertical transmission of HIV-1 infection.

This study assesses the predictive value of the ratio of HIV-1 antibodies in the newborn at birth to that in the mother for perinatally transmitted infection confirmed subsequently by age 18 months. The ratio of HIV-1 (EIA) antibody levels in the baby at birth to that in the seropositive mother after the first trimester (sequenstration index SI) was available in 114 of a perinatal cohort of 137 infants. We related this ratio to the HIV infection status of the children by 18 months, HIV-1 DNA PCR and HIV-specific IgA antibody detection at birth, between 3 and 6 months, and morbidity and mortality. Thirty-five of the 137 (26 per cent) children were diagnosed as infected by 18 months. The mean (SD) HIV SI was 1.57 (0.88) in 29 infected and 0.83 (0.42) in 85 uninfected infants (P < 0.0001). Sensitivity and specificity of a threshold SI of 1.27 (mean +/- 2 SD of uninfected group) for the prediction of perinatal HIV-1 infection were 41 and 98 per cent, respectively. The reason for the higher SI in the infected babies is the combination of lower antibody titres in the transmitting mothers with raised levels in the infected babies. A similar analysis of antibody ratios showed no statistical differences for measles and tetanus (P > 0.1) between HIV infected and uninfected groups. There was a tendency to increased morbidity (Pearson's correlation coefficient r = 0.31) and more severe disease in those with higher HIV-1 SI. Three of 17 (18 per cent) peripheral blood samples from infected children at birth were PCR positive; all had SI's above the threshold. Overall sensitivity and specificity of PCR were 85 per cent each. Eleven of the 29 infected children were HIV-1 specific IgA positive at birth; six (64 per cent) of these had an SI > 1.27. This simple SI of HIV-1 EIA antibodies at birth is comparable to elaborate techniques in its power to predict perinatally acquired infection. It may be a cheap, reliable and rapid screening test for vertically transmitted HIV-1 infection.

HIV-1 specific immunoglobulin A antibodies as an effective marker of perinatal infection in developing countries.

HIV-1 specific IgA antibody testing using commercially available reagents was evaluated at birth to 15 months in a group of infants born to HIV-seropositive South African women. Following IgG depletion of serum samples, 33/35 (94 per cent) of the infected infants and 3/99 (3 per cent) of the uninfected infants showed positive IgA reactivity. Sensitivity at birth was 24 per cent and improved with age; 82 per cent at 3 months, 87 per cent at 6 months and 94 per cent at 12 months. The overall positive and negative predictive values were 92 and 98 per cent, respectively. An evaluation of IgA and PCR in a subsample of infants indicated a better sensitivity of PCR within 3 months of birth, but IgA detection offered a higher overall sensitivity (87 v. 83 per cent) and specificity (91 v. 85 per cent). No significant difference in IgA level was observed between transmitting mothers and non-transmitting mothers. A moderate correlation existed between IgA level in the infant and the cumulative morbidity score, however a stronger association was observed between high IgA levels in the infected infant and rapid disease progression. The viral specific IgA assay is a simple, reliable and cost-effective diagnostic and prognostic test for perinatal HIV infection in developing countries.

Age-related pattern of immunoglobulins G, A and M in children born to HIV-seropositive women.

In a cohort of 56 children born to HIV-seropositive African women, 19 met the criteria for HIV-infected children and 37 remained antibody-negative at 18 months of age. Blood samples taken at birth and 3-monthly until 18 months of age were processed and analysed by laser nephelometry for serum immunoglobulin (IgG, IgA and IgM) levels. In the infected group of children. higher levels of IgG were observed during their 1st 18 months of life reaching statistical significance at 3, 6, 15 and 18 months. Higher levels of IgA at 3 months and at 15 and 18 months, and higher levels of IgM at 3 months and 18 months later were statistically significant. All four infected children who died before the age of 6 months showed signs of hypergammaglobulinaemia (IgG and IgA) by 3 months of age. In this study the earliest and most common immunological abnormality was hypergammaglobulinaemia and infected infants with higher morbidity and mortality had more evident immunoglobulin abnormalities than infected children who survived. However, the immunological abnormalities in this small cohort did not precede the onset of severe symptoms and cannot therefore be used to predict clinical outcome.

Use of HIV-1 specific immunoglobulin G3 as a serological marker of vertical transmission.

The objective of the study was to indicate HIV infection in infants. The patients were part of a longitudinal cohort of 43 infants born to HIV seropositive mothers. A modified Genelavia EIA primarily directed against HIV envelope proteins was used. An alkaline phosphatase labelled IgG3 conjugate was substituted in place of the kit conjugate. HIV specific IgG3 clearance was optimal at 6 months, whilst HIV total antibody was reliable only from age 12 months onwards. At 6 months no detectable IgG3 were found in 91 per cent of uninfected infants where more of these infants had reduced their total HIV antibody titres at the same period. We confirm that HIV specific IgG3 measurement is a reliable and cost effective means of identifying HIV infected infants from 6 months of age onwards.

beta 2-Microglobulin and CD4/CD8 ratio as HIV-1 markers of maternal transmissibility, neonatal infection and disease progression.

A hospital-based cohort study assessing the function of surrogate markers (beta 2-microglobulin and CD4/CD8 ratio) in predicting maternal HIV transmissibility and disease progression in infants was conducted in 110 seropositive black South African mother-infant pairs. There were no differences in beta 2-microglobulin (beta 2-M) levels between the 27 transmitting and 83 non-transmitting mothers (P = 36). beta 2-M levels were higher in the infected that in the uninfected infants, but were significantly higher at 1 month (P = 0.04) and again at 12 months (0.03). A CD4/CD8 ratio < 1 was increasingly reported in the infected infants from 3 months (60.9%) to 15 months (93.8%) of age, and in three (5.4%) uninfected infants. Of the eight infected infants who rapidly progressed to death by 9 months, increased beta 2-M levels at birth and 1 month and inverted CD4/CD8 ratios at 3 months were strongly associated with the objective morbidity score. However, the CD4/CD8 ratio (positive predictive value 82.4%, negative predictive value 82.8%) at 3 months or later remained a better indicator of disease progression than beta 2-M (positive predictive value 33.3%, negative predictive value 74.4%).

Predicting perinatal human immunodeficiency virus infection by antibody patterns.

The evolution of human immunodeficiency virus type 1 (HIV-1) antibody titers determined by enzyme-linked immunosorbent assay between birth and 18 months of age was investigated in 118 babies born to HIV-1-seropositive South African mothers. By 18 months 41 (34.7%) children were diagnosed as HIV-1-infected by standard criteria. All 77 uninfected babies cleared maternal antibodies by 15 months; 94.5% of these babies seroreverted by 12 months. By 9 months of age a significant difference (P < 0.05) was noted between antibody decay rates in infected and uninfected children. Of the children subsequently shown to be uninfected, 95.8% demonstrated > or = 50% decay in antibody titers between 6 and 9 months; only 1 in the infected group showed a similar pattern (sensitivity, 97.8%; specificity, 93.8%). The approach of assessing the progression of antibody decay in infected and uninfected babies makes it a feasible and useful tool for estimating vertical transmission rates and diagnosis of perinatal HIV-1 infection earlier than standard practice.

The effects of vitamin A supplementation on the morbidity of children born to HIV-infected women.

OBJECTIVE: The effects of vitamin A supplementation on morbidity of children born to human immunodeficiency virus (HIV)-infected women were evaluated in a population where vitamin A deficiency is not endemic. METHODS: A randomized, placebo-controlled trial of vitamin A supplementation was carried out in 118 offspring of HIV-infected women in Durban, South Africa. Those assigned to receive a supplement were given 50,000 IU of vitamin A at 1 and 3 months of age; 100,000 IU at 6 and 9 months; and 200,000 IU at 12 and 15 months. Morbidity in the past month was then recalled at each follow-up visit. Analysis was based on 806 child-months. RESULTS: Among all children, the supplemented group had lower overall morbidity than the placebo group (OR = 0.69; 95% confidence interval [CI] = 0.48, 0.99). Among the 85 children of known HIV status (28 infected, 57 uninfected), morbidity associated with diarrhea was significantly reduced in the supplemented infected children (OR = 0.51; 95% CI = 0.27, 0.99), whereas no effect of supplementation on diarrheal morbidity was noted among the uninfected children. CONCLUSION: In a population not generally vitamin A deficient, vitamin A supplementation for children of HIV-infected women appeared to be beneficial, reducing morbidity. The benefit was observed particularly for diarrhea among HIV-infected children.

Some early observations on HIV infection in children at King Edward VIII Hospital, Durban.

Nine black children aged between 3 months and 30 months of age, with human immunodeficiency virus type I (HIV-I) infection are described to draw the attention of health professionals in southern Africa to special clinical characteristics useful for recognising this problem, which has many shared features with common diseases of infancy and childhood in the Third World. The main presenting complaints were chronic cough and persistent diarrhoea and vomiting. These children frequently had diarrhoea (8 of 9 patients), mucocutaneous candidiasis (8), pneumonia (7), hepatosplenomegaly (9), significant lymphadenopathy (5) and wasting (5). All were infected by common bacteria, such as Gram-negative organisms, Mycobacterium tuberculosis and Campylobacter jejuni, or by opportunistic infections such as Candida or cytomegalovirus (CMV), or by both bacterial and opportunistic organisms. A raised total serum globulin level, anaemia, lymphopenia and a cerebrospinal fluid (CSF) pleocytosis were frequent findings. Incomplete data on parental HIV status suggest perinatal transmission. Three of the children were HIV-antigen positive. The diagnosis of full-blown acquired immunodeficiency syndrome (AIDS), using the stringent Centers for Disease Control criteria, is difficult in our situation because of limited diagnostic resources; however, using these criteria, and the clinical case definition for AIDS recommended by World Health Organisation, it is thought that probably 4 of these children could be considered as having AIDS.(ABSTRACT TRUNCATED AT 250 WORDS)

Therapeutic drug monitoring in a paediatric epilepsy clinic.

In 1988 a therapeutic drug monitoring programme for anticonvulsants was introduced in the paediatric neurology clinic at King Edward VIII Hospital, Durban. Although before this serum drug levels were routinely measured, the new approach involved the application of clinical pharmacokinetics to the results so that an individualised drug profile was available for use in conjunction with clinical evaluation at the patient's next visit. Case reports are presented to illustrate the value of using serum levels in this way. Of the 58 patients entered into the study in the course of 1 year, 32 (55%) benefited from the monitoring programme in that the pharmacokinetic report contributed to a dosage adjustment that resulted in a reduction in either seizure frequency or side-effects. The greatest value of the programme proved to be in rationalizing the use of phenytoin. Because of wide inter-patient variation and non-linear kinetics, it is difficult to establish an optimum maintenance dose for this drug. The individualised dose achieved in the present study using Bayesian forecasting resulted in improved seizure control in 10 of the 11 patients (91%) receiving phenytoin.