Paediatrics and Child Health

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The accuracy, sensitivity and specificity of rapid point-of-care testing for CD4+ T cell count enumeration and TB diagnosis.
(2014) Skhosana, Mandisa.; Kiepiela, Photini.; Coutsoudis, Anna.
Objectives: The PIMA CD4+ T cell count analyser has been favourably evaluated for use in point-of-care (POC) situations in Mozambique and Zimbabwe, has also been recommended by the World Health Organisation (WHO), however, there is limited information on its use in Primary Healthcare (PHC) settings in KwaZulu Natal (KZN) South Africa. The main aim of this study therefore assessed the accuracy, sensitivity and specificity of the Alere PIMA Point of Care (POC) analyser CD4+ T cell count enumeration compared to the South African National Health Laboratory Services (SA-NHLS) methodology, which uses Beckman Coulter with Panleucogating (PLG/CD4). The potential role of using the PIMA CD4 analyser as a predictor of antiretroviral therapy (ART) eligibility was also assessed. Material and Methods: The study took place at Lancers Road clinic, a busy primary health clinic (PHC) facility under the eThekwini Health Unit. An extra two millilitres of venous blood was drawn from the same blood draw as for the routine CD4 NHLS test (Beckman Coulter) into another EDTA tube for the comparison of the enumeration of CD4+ T cells using the PIMA analyser during January – July 2013. Results: A total of 268 patients were recruited for the PIMA analyser comparison with NHLS PLG/CD4 while a sub-set of 100 blood samples were also analysed on the FACS calibur. In the 100 samples the PIMA analyser results correlated better with the FACS calibur results (mean bias of 7.52, Bland Altman limits of agreement -111 to 126 and correlation of 0.970) than with the NHLS PLG/CD4 results (mean bias of -12.78, Bland Altman limits of agreement -226.041 to 200.481 and correlation of 0.90). In the 268 samples the overall mean difference between the PIMA analyser – NHLS PLG/CD4 was 17.5 cells/μl (95% CI 6.2 to 28.8). The percentage similarity (SIM) between the two (Mean ± SD) was 106 ± 15.5; indicative of acceptable agreement between the two tests. When categorised by the following CD4+ T cell counts of: ≤350 cells/μl; 351-500 cells/μl; ≤500 cells/μl and > 500 cells/μl , the mean difference of PIMA analysers – NHLS PLG/CD4 was 33 cells/μl (95% CI 23 to 42); 22 cells/μl (95% CI -3.5 to 47); 30 cells/μl (95%CI 21 to 39); and cells/μl (95% CI -78 to 6.1) respectively. Under the current South African guidelines of ≤350 cells/μl CD4+ T cells, the sensitivity of the PIMA analyser was 83.5% and specificity 92%. At this threshold of ≤ 350 cells/μl there were 35 (13%) misclassifications, of which 27 were false negatives. This implies that 27 patients would have been falsely deemed ineligible for ART according to the PIMA analyser. The mean difference between the PIMA analyser and NHLS PLG/CD4 in this group of 27 patients was 112 cells/μl. The positive predictive value was high at 95% such that 95% of the patients eligible for treatment according to PIMA analysers would have also been deemed eligible for treatment on the NHLS PLG/CD4 test. Using future South African treatment guidelines threshold of CD4+ T cell counts ≤500 cells/μl , a high sensitivity of 94% was observed at the sacrifice of lower specificity of 78%. According to the NHLS PLG/ CD4 test result, 164/268 (61%) of patients were eligible for ART (CD4+ T cell count ≤350 cells/μl) compared to 145/268 (54%) with the PIMA analyser POC CD4+ T cell test. Of those eligible for ART according to the ART register at Lancers Road PHC, 110/164 (only 67%) of these patients were initiated on ART. Of those who did not return for their results 35/268 (13%), twenty of 35 (57%) were eligible for ART according to the NHLS PLG/CD4 laboratory CD4 test result, all of whom were not initiated on ART. Conclusion: The overall agreement between the PIMA analyser POC and NHLS PLG/ CD4+ T cell count enumeration in adult HIV positive individuals was acceptable with clinically insignificant mean bias. Together with high positive predictive value, and sensitivity and acceptable specificity the PIMA analyser POC lends itself to an excellent facilitator of improved healthcare.
The association of early neonatal feeding on clinical outcomes and cytotoxic T lymphocyte (CTL) responses in HIV exposed low birth weight infants.
(2011) Dassaye, Reshmi.; Coutsoudis, Anna.; Sunpath, Henry.
BACKGROUND Sub-saharan Africa remains to date at the forefront of the HIV/AIDS epidemic. Despite breastfeeding being a significant mode of postnatal HIV transmission it remains the main nutritional source and pillar of child survival for the majority of infants born in Africa. It is therefore, not surprising that considerable research has centred on making breastfeeding safer in terms of HIV transmission. The flash heat treatment method (HTEBM) provides a unique opportunity to safely breastfeed infants but prevent mother-to-child transmission of HIV. Cytotoxic T lymphocyte (CTL) responses have been well documented in HIVinfected adults and children. However, there is a lack of literature on CTL responses in HIV exposed low birth weight infants. This pilot study attempted to examine the association of early neonatal feeding on the clinical outcomes and CTL responses in HIV exposed low birth weight infants. METHODS Seventy-seven patients that fulfilled inclusion and exclusion criteria were enrolled. The clinical outcomes of these patients were evaluated over a 9 month period. Fifty-five of these patients were also investigated for cytotoxic T lymphocyte (CTL) responses by means of the IFNγ ELISpot (megamatrix and confirmation) assays at the 6 weeks, 3, 6,and 9 months follow-up. RESULTS Two HIV-1 infected infants generated a CTL response at a single time point using the ELISPOT matrix screening assay. These responses could not be confirmed and were undetectable at any of the consecutive visits. At the time of detection of responses the infants were fed unheated breastmilk. HIV-1 exposed uninfected infants were unable to elicit a HIV-1-specific CTL response irrespective of feed. With regards to clinical outcomes, infants born o HIV infected mothers with a CD4 count < 500cells/μl were 2x more likely to acquire other infections at birth compared to those infants born to HIV infected mothers with a CD4 count >500cells/μl. Also, infants born to HIV infected mothers with advanced disease (CD4 count 0-200 cells/μl) had a lower birth weight compared to infants born to HIV-1 infected mothers with a CD4 count > 350 cells/μl. We also investigated the feasibility of the flash heat treatment method at birth. While inhospital, 38 HIV-1 infected women fed their infants HTEBM after receiving counseling and support from the nursing staff at the King Edward VIII hospital. The numbers decreased rapidly post hospital discharge, mainly due to mixed feeding. DISCUSSION In conclusion we have shown that it is feasible for HIV infected mothers to heat treat their expressed breastmilk during hospital admission. Furthermore, we were able to demonstrate in this small cohort of patients that the clinical outcomes and growth parameters of infants fed HTEBM were similar to that of infants fed either formula or unheated breastmilk. We were unable to demonstrate HIV-specific responses in the infected infants or the uninfected infants who had been exposed to heat inactivated virus in HTEBM. Our findings indicate that this pilot study was limited in its ability to detect CTL responses in HIV exposed low birth weight infants and further studies are warranted.
Effect of infant feeding mode and maternal nutritional supplementation on the nutrition and health of HIV positive mothers and their infants.
(2012) Kindra, Gurpreet.; Coutsoudis, Anna.
Background: Breastfeeding is known to have benefits both for maternal and child health. Some questions around the benefits and risks of breastfeeding in the presence of HIV infection still remain unclear. Aims: To study the effects of infant feeding mode by HIV-positive mothers, on maternal and child health. In addition, to assess the effect of nutritional supplementation to HIV-positive lactating mothers on nutritional and health status of mothers and their infants and on the quality of breastmilk. Methods: The study had 2 components; a prospective study to examine the impact of infant feeding mode on nutritional and health indices in mothers and their infants and within it a nested randomized controlled clinical trial to study the impact of a daily 50 g soya/peanut based supplement during breastfeeding on the above parameters. The measurements included anthropometry; body composition indicators (using both deuterium dilution and BIA); haematology and biochemical markers; as well as incidence rates of opportunistic infections and clinical disease progression. Breastmilk was analysed for both macro and micronutrients. Cervical screening was offered to all the women. Results: AFASS criteria were fulfilled by 38.7% of the formula feeding mothers. No significant differences between the formula feeding and breastfeeding groups in terms of haematological, immunological and body composition changes were seen. Breastfeeding mothers had significantly lower events with high depression scores (p=0.043). Longer duration of breastfeeding was observed to be significantly associated with a mean increase in CD4 count (74 cells/μL) and better health outcomes. The supplement made no significant impact on any maternal or child outcomes except for a limited effect on mothers with low BMI, where it was significantly associated with preventing loss of lean body mass (p=0.026). Breastfeeding infants had a significantly lower risk of diarrhoea and hospitalisation at 3 months (p=0.006 and 0.014 respectively). Both breastfeeding and longer duration of breastfeeding was significantly associated with better development scores and growth parameters. Supplementation made no impact on breastmilk composition. Of the 86 mothers who agreed for cervical screening, 27.6% had human papilloma virus infection. Conclusions: Breastfeeding is not harmful to the mother despite the presence of HIV infection. On the contrary we observed both breastfeeding and longer breastfeeding duration to be associated with better maternal and child outcomes. Mothers are still choosing formula feeding inappropriately presumably because of the availability of free formula and/or sub-optimal counseling. The new (2010) local PMTCT guidelines based on WHO recommendations should reverse this. Food insecurity was prevalent amongst 32% of our study population, highlighting the need to include sustainable and empowering solutions to encounter this problem. Less sustainable solutions such as nutritional supplementation should be targeted to the malnourished and in emergency situations.
Epidemiological and clinical studies of vitamin A in Black South African pre-school children.
(1993) Coutsoudis, Anna.
The ocular complications of vitamin A deficiency have been known for many years, however, recent studies have suggested that marginal vitamin A status enlarges the risk of common childhood infections and increases mortality. It is therefore important to assess the vitamin A status, and some of its consequences, in children who are most likely to be at risk for vitamin A deficiency as this has important implications for promoting the health of children and for formulating appropriate primary health care policies. In South Africa very little data is available on vitamin A nutrition of communities; therefore one of the objectives of this research programme was to document the vitamin A status of African children who, because of historical inequities, are most likely to be at risk for deficiency. Sound, epidemiologically based surveys of vitamin A intake and body levels were conducted in a typical established township (using dietary intake as the measuring tool) and in a typical peri-urban informal settlement (using serum retinol and conjunctival impression cytology as the measuring tools). These studies revealed that the majority (97%) of children living in the established township surveyed had an adequate intake of vitamin A, whereas 44% of the children in the informal settlement had low serum retinol levels (20 ug/dL), and 18% had insufficient vitamin A, as assessed by 2 abnormal disc specimens, using the conjunctival impression cytology test. In order to investigate the interrelationsnips between vitamin A, other micronutrients and some risk factors, an analysis was undertaken of anthropometry, parasite infestation and blood concentrations of vitamin E, calcium, magnesium, phosphorous, albumin, haemaglobin, serum iron and ferritin and percent transferrin saturation. Significant positive correlations were found between serum retinol and all the biochemical indicators of iron metabolism studied except for serum ferritin. Ninety one percent of the children sampled were infested with parasites. These results highlight the fact that in this population close interconnections exist among nutrients and suggest that attempts at correcting vitamin A deficiency in such communities should be based on comprehensive intervention programmes rather than on single nutrient replacement. The impact of infections on blood levels of vitamin A was investigated in African children with severe measles. In addition, substances related to vitamin A metabolism such as other micronutrients (zinc, vitamin E) and proteins (retinol binding protein, prealbumin, albumin) were measured in serum. In addition the changes induced in these substances by vitamin A supplementation (offered in a randomised, double blind, placebo controlled trial) were studied. Serum retinol as well as the other nutrients measured were significantly reduced early in the exanthem in measles patients as compared to healthy controls. Vitamin A and prealbumin levels on day 8 (of the intervention trial) were significantly increased in the supplemented group compared to the placebo group. vitamin A levels in serum correlated with those of retinol binding protein (RBP), prealbumin and zinc. These findings strengthen the hypothesis that hyporetinaemia during measles is the consequence of impaired mobilisation of retinol stores from the liver. The effect of reversing the temporary lowering of serum retinol concentrations during acute measles infections by supplementation with vitamin A was investigated in a hospital based, randomized, double-blind, placebo controlled trial. The two groups were comparable in known covariates of measles severity : weight/age centiles; overcrowding; rash; total 90% of the patients had blood lymphocytes; serum levels pre-albumin, RBP, vitamins A and E. of zinc, albumin, hyporetinaemia. Integrated Morbidity Scores ( IMS) derived from diarrhoea, herpes and respiratory tract infection (radiologically confirmed) were assigned on day 8, at 6 weeks and 6 months - these were reduced by 82%, 61% and 85% respectively in the supplemented group. This was mainly due to reduced respiratory tract infection. There was one death in the placebo group. At 6 weeks there was significant weight gain in the supplemented group. Despite the selected sample, attention to multiple covariates enhances the validity of the data obtained and supports the current WHO recommendations for vitamin A supplementation during measles. There are several mechanisms by which vitamin A is thought to have its effect of reducing morbidity, one of which is by improving immune responsiveness. This particular mechanism has not been adequately studied in children; most of the studies having been conducted in animals. The effect of vitamin A supplementation on selected factors of immunity in African children with complicated measles was therefore investigated during the randomized double-blind, placebo controlled, intervention trial described above. Placebo and treated groups had similar baseline characteristics. In the treated group there was a significant increase in total number of lymphocytes (day 42, P = .05) and measles IgG antibody concentrations (day 8, p = .02), both of which have consistently been shown to correlate more closely with outcome in measles than other immunological, clinical and radiological factors. Interleukin-2 (IL-2) and plasma complement (C3 ) values were unaffected by vitamin A supplement.at.Lon , These findings reinforce results from animal studies which show that the pathways of vitamin A activity in decreasing morbidity and mortality are partly founded on selective immunopotentiation. In conclusion epidemiological and biochemical methods which were used to assess the vitamin A status of African children in South Africa revealed that overt vitamin A deficiency is not a Public health issue to the extent it is in the poor rice eating nations of the world. Marginal vitamin A deficiency is however prevalent in informal settlements. Interventions to reverse this marginal vitamin A deficiency should be incorporated in comprehensive programmes to ensure food security. Infections such as measles which increase utilisation and inhibit mobilisation from body stores are damaging to vitamin A homeostasis in the individual. The morbidity associated with measles can be reversed by high dose vitamin A supplementation during the acute phase of the infection. Improving immune responsiveness is one of the likely paths of vitamin A activity in decreasing morbidity from measles.
Evaluation of an exclusive breastfeeding promotion programme in an informal settlement in Durban.
(2002) Bentley, Jane.; Coutsoudis, Anna.
Abstract available in PDF.
Optimum timing for vitamin A supplementation in children with diarrhoea.
(2001) Elson, Karin Inga.; Coutsoudis, Anna.
Vitamin A has well recognised benefits for the reduction in severity of diarrhoeal episodes but the impact of therapeutic doses given during diarrhoea on the biochemical and clinical outcomes is less clear. In this study these potential therapeutic benefits were investigated to establish the optimum time for vitamin A supplementation to improve vitamin A status. Establishing the optimum time for vitamin A supplementation during an infectious stage would improve cost effectiveness and clinical benefit. Young children (174) between the ages of 3 and 60 months with severe diarrhoea were randomised in a double - blinded placebo controlled trial into one of 2 groups. The 1 st group received 60 mg of retinol as retinyl palmitate on admission during the acute diarrhoeal stage. The 2nd group received the same dose of vitamin A once symptoms had resolved, usually between 3 - 7 days. At each of these two time points, children not receiving vitamin A were given an identical placebo dose. Baseline (day 0) and day 3 serum samples were collected for vitamin A, retinol binding protein (RBP) and other biochemical markers. At four and eight weeks after discharge both morbidity and weight gain were recorded. The modified dose response test (MRDR) was conducted at the eight - week follow - up to estimate vitamin A liver stores. Initially, most of the children presented with watery diarrhoea and dehydration and were clinically very ill. At day 3 plasma retinol concentrations improved in both groups viz. from 0.57umol/L to 0.97umol/L in the 1st group and from 0.49umol/L to 0.90umol/L in the 2nd group. Similar improvements were found in retinol binding protein viz. 21.28 mg/L to 31.06 mg/L in the 1st group and 17.05 mg/L to 24.80 mg/L in the 2nd group. At 8 weeks there was also no significant difference between the two groups either for serum retinol (0.69umol/L and 0.73umol/L respectively) nor for MRDR ratios (0.036 and 0.049 respectively). The MRDR results at 8 weeks indicated that these children did not have depleted vitamin A liver stores and that the low serum retinol levels seen at baseline were probably due to the acute phase response during an infectious episode. The results of these analyses showed no significant difference between the two treatment groups thus indicating that there was no benefit to giving vitamin A on recovery from an infectious episode instead of on admission, as is currently practised.

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