Tygerberg Children's Hospital Research Articles

Pulse wave velocity in early-treated children living with perinatal HIV infection is similar to uninfected children.

HIV is associated with accelerated cardiovascular disease, due to HIV-associated metabolic abnormalities, antiretroviral therapy (ART), and HIV itself. Carotid-femoral pulse wave velocity (PWV) is the noninvasive gold standard measurement of arterial stiffness, and associated with incident vascular events in adults. It is unclear if arterial stiffness is accelerated in children living with perinatal HIV (CHIV) who initiate ART early in life. We compared the longitudinal trajectory of PWV in CHIV to children unexposed to HIV. A secondary comparison compared HIV exposed uninfected children (CHEU) to unexposed children. Four hundred and sixty-five children (141 CHIV, 160 CHEU, 164 unexposed) previously in the children with HIV early antiretroviral therapy (ART) (CHER) and P1060 trials were followed annually at Tygerberg Children's Hospital, South Africa between 2014 and 2020. CHIV initiated ART in infancy or early childhood, with excellent ART adherence and largely sustained viral suppression. The primary outcome was PWV, measured using the Vicorder system, and evaluated using linear mixed effects models. Median (interquartile range) age at first PWV measurement was 8.64 (7.7-9.1) years, and median follow-up time 2.9 (1.6-4.0) years. Adjusted analyses showed no significant mean difference in PWV in CHIV and CHEU compared to unexposed [CHIV: 0.101 m/s, 95% confidence interval (CI) -0.012 to 0.214; CHEU: 0.068 m/s, 95% CI -0.047 to 0.183], after adjusting for gender, age, ethnicity, mean arterial pressure, resting average heart rate and family history of cardiovascular disease. Early-treated CHIV with sustained viral suppression have similar PWV to unexposed children. Excellent adherence and early ART initiation may protect against cardiovascular disease.

Longitudinal comparison of insulin resistance and dyslipidemia in children with and without perinatal HIV infection in South Africa.

HIV infection is associated with insulin resistance and dyslipidaemia driven by HIV-associated immune dysregulation and antiretroviral therapy (ART). Children living with perinatally acquired HIV (CHIV) face many decades of exposure to these factors. We evaluated the longitudinal trajectory of insulin resistance and dyslipidaemia in CHIV and HIV-exposed uninfected children (CHEU), compared with children HIV-unexposed (CHU). Four hundred and eighty-five children (141 CHIV, 169 CHEU, 175 CHU) aged 5-16 years, previously part of CHER and P1060 trials, were followed annually at Tygerberg Children's Hospital, South Africa. The primary outcome was Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Secondary outcomes included low-density lipoprotein (LDL) cholesterol, triglyceride-to-HDL ratio, android fat mass and SBP. Outcomes were evaluated using linear mixed effects models, adjusting for potential confounders. CHIV had 73% greater HOMA-IR than CHU in ages 6-8 years (95% CI 15.9-158.2%, P < 0.001), and 24.7% greater HOMA-IR than CHU in ages 9-10 years (0.3-55.1%, P = 0.04). By 10-11 years, the difference was not significant (P = 0.161). Longitudinally, triglyceride-to-HDL was 47.94% (34.50-62.73%, P < 0.001) higher in CHIV vs. CHU; LDL was 0.25 mmol/l (0.10-0.39, P = 0.001) higher in CHIV vs. CHU; android fat mass was 11.57% (-21.11 to -0.87%, P = 0.035) lower in CHIV than CHU. No significant difference in SBP was found. CHEU and CHU had similar outcomes. Early-treated CHIV have elevated insulin resistance, which resolves with time. Triglyceride-to-HDL ratio and LDL cholesterol were elevated into puberty. CHIV should be monitored for insulin resistance, dyslipidaemia and subclinical cardiovascular disease.

Bioreactance-derived haemodynamic parameters in the transitional phase in preterm neonates: a longitudinal study.

Bioreactance (BR) is a novel, non-invasive technology that is able to provide minute-to-minute monitoring of cardiac output and additional haemodynamic variables. This study aimed to determine the values for BR-derived haemodynamic variables in stable preterm neonates during the transitional period. A prospective observational study was performed in a group of stable preterm (< 37weeks) infants in the neonatal service of Tygerberg Children's Hospital, Cape Town, South Africa. All infants underwent continuous bioreactance (BR) monitoring until 72h of life. Sixty three preterm infants with a mean gestational age of 31weeks and mean birth weight of 1563g were enrolled. Summary data and time series graphs were drawn for BR-derived heart rate, non-invasive blood pressure, stroke volume, cardiac output and total peripheral resistance index. All haemodynamic parameters were significantly associated with postnatal age, after correction for clinical variables (gestational age, birth weight, respiratory support mode). To our knowledge, this is the first paper to present longitudinal BR-derived haemodynamic variable data in a cohort of stable preterm infants, not requiring invasive ventilation or inotropic support, during the first 72h of life. Bioreactance-derived haemodynamic monitoring is non-invasive and offers the ability to simultaneously monitor numerous haemodynamic parameters of global systemic blood flow. Moreover, it may provide insight into transitional physiology and its pathophysiology.

Central-line-associated bloodstream infections in a resource-limited South African neonatal intensive care unit.

The rate of central-line-associated bloodstream infection (CLABSI) in South African (SA) public sector neonatal intensive care units (NICUs) is unknown. Tygerberg Children's Hospital (TCH), Cape Town, introduced a neonatal CLABSI surveillance and prevention programme in August 2012. To describe CLABSI events and identify risk factors for development of CLABSI in a resource-limited NICU. A retrospective case-control study was conducted using prospectively collected NICU CLABSI events matched to four randomly selected controls, sampled from the NICU registry between 9 August 2012 and 31 July 2014. Clinical data and laboratory records were reviewed to identify possible risk factors, using stepwise forward logistic regression analysis. A total of 706 central lines were inserted in 530 neonates during the study period. Nineteen CLABSI events were identified, with a CLABSI rate of 5.9/1 000 line days. CLABSI patients were of lower gestational age (28 v. 34 weeks; p=0.003), lower median birth weight (1 170 g v. 1 975 g; p=0.014), had longer catheter dwell times (&gt;4 days) (odds ratio (OR) 5.1 (95% confidence interval (CI) 1.0 - 25.4);p=0.04) and were more likely to have had surgery during their NICU stay (OR 3.5 (95% CI 1.26 - 10); p=0.01). Significant risk factors for CLABSI were length of stay &gt;30 days (OR 20.7 (95% CI 2.1 - 203.2); p=0.009) and central-line insertion in the operating theatre (OR 8.1 (95% CI 1.2 - 54.7); p=0.03). Gram-negative pathogens predominated (12/22; 54%), with most isolates (10/12; 83%) exhibiting multidrug resistance. The TCH NICU CLABSI rate is similar to that reported from resource-limited settings, but exceeds that of high-income countries. Prolonged NICU stay and central-line insertion in the operating theatre were important risk factors for CLABSI development. Intensified neonatal staff training regarding CLABSI maintenance bundle elements and hand hygiene are key to reducing CLABSI rates.

Infectious disease exposures and outbreaks at a South African neonatal unit with review of neonatal outbreak epidemiology in Africa

Hospitalized neonates are vulnerable to infection, with pathogen exposures occurring in utero, intrapartum, and postnatally. African neonatal units are at high risk of outbreaks owing to overcrowding, understaffing, and shared equipment. Neonatal outbreaks attended by the paediatric infectious diseases and infection prevention (IP) teams at Tygerberg Children's Hospital, Cape Town (May 1, 2008 to April 30, 2016) are described, pathogens, outbreak size, mortality, source, and outbreak control measures. Neonatal outbreaks reported from Africa (January 1, 1996 to January 1, 2016) were reviewed to contextualize the authors' experience within the published literature from the region. Thirteen outbreaks affecting 148 babies (11 deaths; 7% mortality) over an 8-year period were documented, with pathogens including rotavirus, influenza virus, measles virus, and multidrug-resistant bacteria (Serratia marcescens, Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci). Although the infection source was seldom identified, most outbreaks were associated with breaches in IP practices. Stringent transmission-based precautions, staff/parent education, and changes to clinical practices contained the outbreaks. From the African neonatal literature, 20 outbreaks affecting 524 babies (177 deaths; 34% mortality) were identified; 50% of outbreaks were caused by extended-spectrum β-lactamase-producing Klebsiella pneumoniae. Outbreaks in hospitalized African neonates are frequent but under-reported, with high mortality and a predominance of Gram-negative bacteria. Breaches in IP practice are commonly implicated, with the outbreak source confirmed in less than 50% of cases. Programmes to improve IP practice and address antimicrobial resistance in African neonatal units are urgently required.

Birth Prevalence of Anorectal Malformations for the Western Cape Province, South Africa, 2005 to 2012.

Introduction Anorectal malformations (ARMs) are a major birth anomaly worldwide. South Africa has ethnically and geologically diverse populations. A recent publication indicated an increased birth prevalence of ARMs in the Witwatersrand referral area between 2005 and 2010. The purpose of this study was to determine the birth prevalence of ARM and its various subtypes in the Western Cape referral district over an 8-year period. Methods For an 8-year period from January 1, 2005, to December 31, 2012; retrospective data were collected from the Pediatric Surgical Departments of Red Cross War Memorial Children's Hospital, Tygerberg Children's Hospital, as well as the private sector health registries. The number of live births per year for a specific municipal district was obtained from the National Department of Health. The chi-square for trend test was used to determine statistical significance. Results The birth prevalence for ARM in the Western Cape Province (WCP) in 2012 was shown to be 1:5,572 live births (1.79/10,000 live births). The West Coast municipality district had the highest average birth prevalence rate of 1:3,063 (3.26/10,000) live births for years studied. There was a male predominance (1.6:1), the most common ARM was the vestibular fistula (19.2%) and in 26% of the patients, there was an initial delay in the diagnosis. Conclusion This study has provided some recent data for ARMs for the WCP. There was no statistical significant change in the prevalence of ARMs over the 8-year period for the WCP as well as in any of the individual six municipal health districts (χ2 for trend, p = 0.52). The number of delayed diagnosis of ARM is of concern.

Burden, spectrum, and impact of healthcare-associated infection at a South African children's hospital

SummaryBackgroundIn most African countries the prevalence and effects of paediatric healthcare-associated infection (HCAI) and human immunodeficiency virus (HIV) infection are unknown.AimTo investigate the burden, spectrum, risk factors, and impact of paediatric HCAI by prospective clinical surveillance at a South African referral hospital.MethodsContinuous prospective clinical and laboratory HCAI surveillance using Centers for Disease Control and Prevention (CDC)/National Healthcare Safety Network (NHSN) definitions was conducted at Tygerberg Children's Hospital, South Africa, from May 1st to October 31st in 2014 and 2015. Risk factors for HCAI and associated mortality were analysed with multivariate logistic regression; excess length of stay was estimated using a confounder and time-matching approach.FindingsHCAI incidence density was 31.1 per 1000 patient-days (95% CI: 28.2–34.2); hospital-acquired pneumonia (185/417; 44%), urinary tract infection (UTI) (45/417; 11%), bloodstream infection (BSI) (41/417; 10%), and surgical site infection (21/417; 5%) predominated. Device-associated HCAI incidence in the paediatric intensive care unit (PICU) was high: 15.9, 12.9 and 16 per 1000 device-days for ventilator-associated pneumonia, central line-associated BSI and catheter-associated UTI, respectively. HCAI was significantly associated with PICU stay (odds ratio: 2.0), malnutrition (1.6), HIV infection (1.7), HIV exposure (1.6), McCabe score ‘fatal’ (2.0), comorbidities (1.6), indwelling devices (1.9), blood transfusion (2.5), and transfer in (1.4). Two-thirds of paediatric deaths were HCAI-associated, occurring at a median of four days from HCAI onset with significantly higher crude mortality for HCAI-affected vs HCAI-unaffected hospitalizations [24/325 (7.4%) vs 12/1022 (1.2%); P < 0.001]. HCAI resulted in US$371,887 direct costs with an additional 2275 hospitalization days, 2365 antimicrobial days, and 3575 laboratory investigations.ConclusionHCAI was frequent with significant morbidity, mortality, and healthcare costs. Establishment of HCAI surveillance and prevention programmes for African children is a public health priority.

Assessment of terminal cleaning in pediatric isolation rooms: Options for low-resource settings.

Few studies have evaluated terminal cleaning in low-resource settings. Adequacy of pediatric isolation room terminal cleaning was evaluated using quantitative bacterial surface cultures, ATP bioluminescence assays, and fluorescent high-touch surface markers at Tygerberg Children's Hospital in South Africa (August 1, 2014-October 31, 2015). Cleaning adequacy was assessed by comparing pre- and postcleaning measurements. Influence of verbal feedback was determined by comparing cleaners' first and subsequent cleaning episodes. Cleaning methods were compared for cost, time, and feasibility. Adequacy of terminal cleaning was evaluated in 25 isolation rooms after hospitalization for pulmonary tuberculosis (n = 13), respiratory (n = 5) and enteric viruses (n = 5), pertussis (n = 1), and methicillin-resistant Staphylococcus aureus (n = 1). Mean aerobic colony counts and mean ATP relative light units declined between pre- and postcleaning evaluations (39 ± 41 to 15 ± 30 [P < .001] and 72 ± 40 to 23 ± 11 [P < .001]). Fluorescent marker removal was initially poor, but improved significantly at subsequent cleaning episodes (17 out of 78 [22%] to 121 out of 198 [61%]; P < .001); mean aerobic colony counts and ATP values also declined significantly following feedback. Cost, time, and resources required for ATP and surface cultures far exceeded that required for fluorescent markers. Adequacy of isolation room cleaning improved following feedback to cleaning staff. Fluorescent markers are an inexpensive option for cleaning evaluation and training in low-resource settings.

Retinopathy of prematurity screening criteria and workload implications at Tygerberg Children's Hospital, South Africa: A cross-sectional study.

Screening guidelines for retinopathy of prematurity (ROP) used in high-income countries are not appropriate for middle- income countries, and screening requirements may vary even between units within one city. To determine optimal ROP screening criteria, and its workload implications, for Tygerberg Children's Hospital (TCH), Cape Town, South Africa. This cross-sectional study included premature infants screened for ROP at TCH from 1 January 2009 to 31 December 2014. Logistic regression analysis for prediction and classification was performed. Predictors were birth weight (BW) and gestational age (GA). Endpoints were clinically significant ROP (CSROP) and type 1 ROP (T1ROP). Of 1 104 eligible infants, 33.4% had ROP (CSROP 9.1%, T1ROP 2.5%). All T1ROP infants received laser therapy. The number of screening examinations was inversely correlated with GA and BW. The number needed to screen to identify one infant requiring treatment was 41 (entailing 83 examinations, 4 screening hours, one technician and three doctors). Screening infants with a GA of ≤28 weeks or a BW of &lt;1 000 g would have detected all infants with T1ROP but missed two outliers with CSROP. These outliers would only have been detected with a GA of ≤32 weeks or a BW &lt;1 500 g. Detection of infants with T1ROP is resource intensive. Larger infants require screening to include a few outliers, but they require fewer examinations than smaller infants. Making local screening criteria narrower on the basis of a limited evidence base may be dangerous. Risk factors for CSROP in larger infants need to be researched.

Management of therapeutic hypothermia for neonatal hypoxic ischaemic encephalopathy in a tertiary centre in South Africa

AimTherapeutic hypothermia (TH), shown in developed countries to improve outcome in infants with hypoxic-ischaemic encephalopathy (HIE), was introduced into standard care at Tygerberg Children's Hospital in 2008. We aimed to...

The diagnostic value of cerebrospinal fluid chemistry results in childhood tuberculous meningitis.

Cerebrospinal fluid (CSF) hypoglycorrhachia and elevated protein is well-described in bacterial meningitis, but evidence for its differential diagnostic value in tuberculous meningitis (TBM) is lacking. We aimed to assess the diagnostic utility of CSF glucose, CSF to serum glucose ratio and CSF protein in children with suspected TBM. We describe CSF glucose and protein values as well as CSF to serum glucose ratios in a prospective evaluation of TBM suspects seen at Tygerberg Children's Hospital, Cape Town, South Africa, from January 1985 to January 2014. Of 615 TBM suspects, 88 (14%) had microbiologically confirmed TBM, 381 (62%) 'probable' TBM and 146 (24%) 'non-TBM'. Mean absolute CSF glucose concentration was significantly lower in the microbiologically confirmed (1.87 ± 1.15 mmol/L) and 'probable' TBM (1.82 ± 1.19 mmol/L) groups compared to non-TBM (3.66 ± 0.88 mmol/L). A CSF glucose concentration of <2.2 mmol/L diagnosed TBM with sensitivity 0.68 and specificity 0.96. Sensitivity using a CSF to serum glucose ratio of <0.5 was 0.90. Mean CSF protein was significantly elevated in the microbiologically confirmed TBM (1.91 ± 1.44 g/L) and 'probable' TBM (2.01 ± 1.49 g/L) groups compared to the non-TBM (0.31 ± 0.31 g/L). A CSF protein >1 g/L diagnosed TBM with sensitivity 0.78 and specificity 0.94. Absolute CSF glucose values of <2.2 mmol/L and protein values of >1 g/L differentiated between TBM and non-bacterial meningitis with good specificity, although sensitivity was poor. A CSF to serum glucose ratio is more informative than the absolute value.

Chest radiograph findings in children with tuberculous meningitis.

Tuberculous meningitis (TBM) is diagnosed based on a combination of clinical, laboratory and radiological findings, including signs suggestive of tuberculosis (TB) on a standard chest X-ray (CXR). We describe the radiological features suggestive of intrathoracic TB in children diagnosed with TBM during a prospective evaluation of TBM suspects seen at Tygerberg Children's Hospital, Cape Town, South Africa. Of 84 children treated for TBM, 31 (37%) had 'definite' TBM, 45 (55%) 'probable' TBM and 8 (9%) 'possible' TBM. In total, 37 (44%) TBM patients had CXR findings suggestive of TB, 9 (11%) with disseminated (miliary) TB. Only 1 in 4.39 children aged ≤3 years with TBM had suggestive CXR findings. The presence of complicated intrathoracic lymph node disease was significantly higher in children aged ≤3 years (OR 21.69, 95%CI 2.73-172.67, P < 0.01). Among 6 human immunodeficiency virus infected children, 3 (50%) had intrathoracic lymphadenopathy. The majority of the children with TBM, including the very young, did not have signs suggestive of TB on CXR.

Uniform Research Case Definition Criteria Differentiate Tuberculous and Bacterial Meningitis in Children

Tuberculous meningitis (TBM) research is hampered by low numbers of microbiologically confirmed TBM cases and the fact that they may represent a select part of the disease spectrum. A uniform TBM research case definition was developed to address these limitations, but its ability to differentiate TBM from bacterial meningitis has not been evaluated. We assessed all children treated for TBM from 1985 to 2005 at Tygerberg Children's Hospital, Cape Town, South Africa. For comparative purposes, a group of children with culture-confirmed bacterial meningitis, diagnosed between 2003 and 2009, was identified from the National Health Laboratory Service database. The performance of the proposed case definition was evaluated in culture-confirmed TBM and bacterial meningitis cases. Of 554 children treated for TBM, 66 (11.9%) were classified as "definite TBM," 408 (73.6%) as "probable TBM," and 72 (13.0%) as "possible TBM." "Probable TBM" criteria identified culture-confirmed TBM with a sensitivity of 86% and specificity of 100%; sensitivity was increased but specificity reduced when using "possible TBM" criteria (sensitivity 100%, specificity 56%). "Probable TBM" criteria accurately differentiated TBM from bacterial meningitis and could be considered for use in clinical trials; reduced sensitivity in children with early TBM (stage 1 disease) remains a concern.

Human Milk Oligosaccharides Differ between HIV-Infected and HIV-Uninfected Mothers and Are Related to Necrotizing Enterocolitis Incidence in Their Preterm Very-Low-Birth-Weight Infants

The heavy burden of maternal HIV infection has resulted in a high prevalence of premature birth and associated necrotizing enterocolitis (NEC). Human milk oligosaccharides (HMOs) were recently associated with HIV infection and transmission through breastfeeding and were also shown to reduce NEC in an animal model, particularly the HMO disialyllacto-N-tetraose (DSLNT). The primary aim of this study was to verify differences in HMO composition between HIV-infected and HIV-uninfected women. The secondary aim was to assess whether the HMO composition in the milk of mothers whose infants were diagnosed with NEC differs from that of mothers whose infants did not develop NEC. This study forms part of a larger clinical trial conducted at the Tygerberg Children's Hospital, Cape Town, South Africa, which recruited HIV-infected and HIV-uninfected mothers and their preterm infants (<34 wk gestation; ≥500 and ≤1250 g). Eighty-two mother-infant pairs were selected for the substudy. Mother-infant pairs were stratified according to the mother's HIV (infected/uninfected) and secretor status (secretor/nonsecretor). HMOs in 4- and 28-d postpartum milk samples were analyzed by HPLC and compared between groups. Our results confirm previous reports that HIV-infected mothers have higher relative abundances of 3′-sialyllactose in their milk compared with HIV-uninfected mothers (10.7% vs. 6.8%; P < 0.01). Most intriguingly, the data also indicated that low concentrations of DSLNT in the 4-d milk samples in the mother's milk increased the infant's risk of NEC (200 ± 126 vs. 345 ± 186 μg/mL; P < 0.05), which is in accordance with results from previously published animal studies and warrants further investigation. This trial was registered at clinicaltrials.gov as NCT01868737.

Severe manifestations of extrapulmonary tuberculosis in HIV-infected children initiating antiretroviral therapy before 2 years of age

BackgroundEarly initiation of antiretroviral therapy (ART) in HIV-infected infants reduces mortality and opportunistic infections including tuberculosis (TB). However, young HIV-infected children remain at high risk of TB disease following mycobacterial...

Pharmacokinetics of Isoniazid in Low-Birth-Weight and Premature Infants

Isoniazid (INH) is recommended for use as posttuberculosis exposure preventive therapy in children. However, no pharmacokinetic data are available for INH treatment in low-birth-weight (LBW) infants, who undergo substantial developmental and physiological changes. Our objectives in this study were to determine the pharmacokinetic parameters of INH at a dose of 10 mg/kg of body weight/day and to define its pharmacokinetics relative to the arylamine N-acetyltransferase-2 (NAT2) genotype. An intensive prospective pharmacokinetic sampling study was conducted at Tygerberg Children's Hospital, South Africa, in which we measured INH blood plasma concentrations at 2, 3, 4 and 5 h postdose. Twenty LBW infants (14 male, 16 exposed to HIV) were studied. The median birth weight was 1,575 g (interquartile range, 1,190 to 2,035 g) and the median gestational age was 35 weeks (interquartile range, 34 to 38 weeks). The NAT2 acetylation statuses of the infants were homozygous slow (SS) (5 infants), heterozygous intermediate (FS) (11 infants), and homozygous fast (FF) (4 infants). Using a noncompartmental analysis approach, the median maximum drug concentration in blood serum (Cmax) was 5.63 μg/ml, the time after drug administration to reach CmaxTmax) was 2 h, the area under the concentration-time curve from 2 to 5 h (AUC2-5) was 13.56 μg · h/ml, the half-life (t1/2) was 4.69 h, and the elimination constant rate (kel) was 0.15 h(-1). The alanine aminotransferase levels were normal, apart from 2 isolated values at two and three times above the normal levels. Only the three-times-elevated value was repeated at 6 months and normalized. All LBW infants achieved target INH blood plasma concentrations comparable to the adult values. Reduced elimination was observed in smaller and younger infants and in slow acetylators, cautioning against higher doses. The safety data, although limited, were reassuring. More data, however, are required for newborn infants.

Lipoarabinomannan enzyme-linked immunosorbent assay for early diagnosis of childhood tuberculous meningitis

Tuberculous meningitis (TBM) is a severe complication of tuberculosis (TB) predominantly affecting young children. Early initiation of treatment is important to prevent morbidity and mortality associated with TBM, emphasising the importance of early diagnosis. Among the most promising new methods for diagnosing TB are antigen-detection assays based on the detection of lipoarabinomannan (LAM). To evaluate the diagnostic value of a commercial, antigen-capture enzyme-linked immunosorbent assay (ELISA) test based on the detection of LAM in urine for the early diagnosis of TBM in children. A cross-sectional study in which urine samples from paediatric patients with suspected TBM attending the Tygerberg Children's Hospital, Cape Town, South Africa, were tested for LAM. Complete data were available for 50 of 56 patients with suspected TBM. TBM was diagnosed in 21 (42%) patients and excluded in 29 (58%). The LAM ELISA had a sensitivity of 4.8% and a specificity of 93.1%. Serial measurements in the first 2 weeks after treatment initiation did not improve test performance. We have shown that urinary LAM detection was of little value for the diagnosis of TBM in a cohort of paediatric patients with suspected TBM.

GeneXpert MTB/RIF on bronchoalveolar lavage samples in children with suspected complicated intrathoracic tuberculosis: A pilot study

Children with complicated intrathoracic tuberculosis (TB) require rapid confirmation of TB diagnosis and of drug susceptibility to institute appropriate therapy. In a pilot study, we evaluated the feasibility and potential utility of GeneXpert (Xpert) on bronchoalveolar lavage (BAL) samples in children undergoing routine diagnostic bronchoscopy. We included children <13 years of age undergoing bronchoscopy for suspected complicated intrathoracic TB at Tygerberg Children's Hospital, October 1, 2012-May 15, 2013. A minimum of two respiratory specimens in addition to BAL were obtained from each child. In addition to fluorescent smear microscopy and automated liquid culture performed on all samples, BAL samples were analyzed by Xpert. Drug susceptibility was confirmed by GenoType(®) MTBDRplus. Fourteen children (2 HIV positive, median age 16 months) were included. The Mantoux tuberculin skin test was positive in 11. On chest radiograph, six children had expansile pneumonia and nine had airway compression (one had both). The median duration of TB treatment before bronchoscopy was 8 days. TB was confirmed by either culture or Xpert from any sample in 11 (78%) children. Among 9/14 (64%) cases confirmed by culture, BAL Xpert was positive in 7 (78% sensitivity); in addition, Xpert confirmed 2 cases who had negative culture (14% additional diagnostic yield). Two drug resistant cases were identified: one by BAL Xpert and one from genotypic testing of a culture from gastric aspirate. All children were initiated on anti-TB treatment and responded well to therapy. BAL Xpert resulted in additional diagnostic yield and also in the rapid detection of drug resistance in children with complicated intrathoracic TB. The clinical impact of this modality should be further evaluated in children.

Are lopinavir and efavirenz serum concentrations in HIV-infected children in the therapeutic range in clinical practice?

Background:In antiretroviral treatment the role of therapeutic drug monitoring via measurement of serum levels remains unclear, especially in children.Aim:To quantify exposure to LPV and EFV in children receiving therapy in a routine clinical setting in order to identify risk factors associated with inadequate drug exposure.Method:A prospective study was conducted in a routine clinical setting in Tygerberg Children's Hospital, South Africa. A total of 53 random serum levels were analyzed. Serum concentrations were determined by an established high-performance liquid chromatography method.Results:Of 53 HIV-infected children treated with lopinavir (n = 29, median age 1·83 y) or efavirenz (n = 24, median age 9·3 years), 12 showed serum levels outside the therapeutic range (efavirenz) or below Cmin (lopinavir). Low bodyweight, rifampicin co-treatment, and significant comorbidity were potential risk factors for inadequate drug exposure.Conclusion:These findings, together with previous studies, indicate that therapeutic drug monitoring can improve the management of antiretroviral therapy in children at risk.

Children With Cancer and HIV Infection

Children with HIV and cancer show an excess of non-Hodgkin lymphoma and leiomyosarcoma when compared with children with malignancy but without HIV. This study aimed at: (1) comparing the distribution of various cancers in South African children with malignancies and HIV versus children with malignancies but without HIV and (2) comparing the outcomes after therapy. This is a retrospective comparative study of 84 black children with cancer and HIV, consecutively admitted at Tygerberg Children's Hospital, Cape Town and Universitas Hospital, Bloemfontein, between 1995 and 2010, compared with 570 HIV-negative black children with malignant diseases, consecutively admitted at the 2 hospitals, between 2002 and 2010. Variables studied included age, sex ratio, number of cases of each malignancy, length of follow-up, treatment abandonment, and mortality. The statistical significance was tested with the Student t test and χ test for P≤0.05. Kaplan-Meyer survival curves were constructed. The most frequent cancer was Kaposi sarcoma (39.3%), seen exclusively in children with HIV. Burkitt lymphoma was found more often (20.2%) in the HIV-positive group than in the HIV-negative one (2.8%, P<0.0001). Leiomyosarcoma, described as the second most frequent neoplasm encountered in HIV-positive children, was found in this series only once. The survival figures are much worse in the HIV-positive group: 26.2% versus 47.7% (P<0.0001), mainly due to drug toxicity. Kaposi sarcoma and Burkitt lymphoma occurred more often in children with HIV. These children have a lower tolerance of chemotherapy, even when combined with HAART.