Comparison of haematology and biochemistry parameters in healthy South African infants with laboratory reference intervals.

OBJECTIVE: Paediatric laboratory reference intervals used in Africa and Asia may be derived from historical intervals of predominantly Caucasian infants in Europe or North America. These intervals may therefore not be compatible with the range of normality for developing country populations. We aimed to compare haematology and biochemistry parameters in healthy South African infants with local laboratory reference intervals. METHODS: We compared the baseline haematology and biochemistry results of 634 (316 male and 318 female) HIV-unexposed infants, aged 3-6 months, living in a rural area of the Western Cape Province, South Africa, against laboratory reference intervals supplied by the South African National Health Laboratory Services (NHLS). We calculated the percentage of observed values out of bound (in terms of lower and upper limits) compared to laboratory reference intervals. RESULTS: Of the 634 healthy infants screened, 316 (49.84%) were male and 318 (50.16%) female. A majority (91.05%) had platelet counts above the laboratory reference interval upper limit (350 × 109 cells/l), while over half, 54.85% and 56.98% had mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH) values below the lower limits of 77.0-105.0 fl and 26.0-34.0 pg, respectively. A small proportion were outside the reference limits for haematocrit, namely 15.71% below and 7.14% above the normal limits of 0.31-0.38 l/l. For male and female infants, 33.65% and 18.04% of alkaline phosphatase (ALP) values and 7.01% and 14.56% of alanine transaminase (ALT) values were above the upper limits, respectively. For male infants, 10.83% of gamma-glutamyl transferase (GGT) values, and for female infants, 31.11% of GGT values were below the lower limits of 12 U/l for males and 15 U/l for females. We observed no significant deviations (>10% out of bound) from NHLS reference intervals in the remaining haematology and biochemistry parameters measured. CONCLUSIONS: Haematology and biochemistry parameters in apparently healthy South African infants deviate frequently from national laboratory reference intervals, including abnormalities consistent with subclinical hypochromic microcytic anaemia. It is important that clinical laboratory reference intervals for children are derived locally, rather than being adopted from Caucasian norms in developed countries, because clinical trials of vaccines, drugs and diagnostics are increasingly conducted in sub-Saharan Africa.

A controlled trial of sputum induction and routine collection methods for TB diagnosis in a South African community.

The diagnostic yield of pulmonary tuberculosis (TB) by sputum induction (SI) at the first point of contact with health services, conducted in all patients with suspected TB regardless of the ability to expectorate spontaneously, has not been evaluated. We compared the diagnostic yield of SI to routine sputum collection in a South African community setting. Ambulatory patients with suspected TB provided a 'spot' expectorated sputum sample, an SI sample by hypertonic (5 %) saline nebulization, and early morning expectorated sputum sample. The diagnostic yield of sputum smear microscopy and liquid culture (denominator all subjects with any positive Mycobacterium tuberculosis culture), and time-to-positivity of culture were compared between SI and expectorated samples. A total of 555 subjects completed the SI procedure, of whom 132 (24 %) were human immunodeficiency virus (HIV)-infected. One hundred and twenty-nine samples (129, 23 %) were M. tuberculosis culture-positive. The time-to-positivity of Mycobacteria Growth Indicator Tube (MGIT) culture was shorter for SI (median difference 2 days, p = 0.63) and for early morning expectorated sputum (median difference 2 days, p = 0.02) compared to spot expectorated sputum. However, there was no difference in the culture-positive diagnostic yield between SI and spot expectorated sputum [difference +0.7 %; confidence interval (CI) -7.0 to +8.5 %, p = 0.82] or SI and early morning expectorated sputum (difference +4.7 %; CI -3.2 to +12.5 %, p = 0.20) for all subjects or for HIV-infected subjects. SI reduces the time to positive M. tuberculosis culture, but does not increase the rate of positive culture compared to routine expectorated sputum collection. SI cannot be recommended as the routine collection method at first contact among ambulatory patients with suspected TB in high-burden communities.

Sputum induction for the diagnosis of pulmonary tuberculosis: a systematic review and meta-analysis.

Sputum induction (SI) has been proposed as the optimal sample collection method for patients with paucibacillary tuberculosis (TB). Studies reporting the culture of Mycobacterium tuberculosis from SI were reviewed. A random-effects meta-analysis of diagnostic yield (numerator M. tuberculosis SI culture-positive cases; denominator all culture-positive cases) was conducted. Diagnostic yields (95% confidence intervals, CIs) were displayed as Forest plots. Heterogeneity was evaluated using Chi-squared and I-squared tests and meta-regression analysis. Ninety publications were screened, 28 full-text papers reviewed, and 17 analyzed. Collectively, n=627 SI culture-positive cases among n=975 culture-confirmed TB cases were reported. The diagnostic yield of SI ranged from 35 to 95%. The pooled diagnostic yield was 74% (CI 65-81%), with significant heterogeneity (p<0.0001, I2=86%). There were no statistically significant differences in the yield between sub-groups defined by human immunodeficiency virus (HIV) prevalence or age. Univariate analysis demonstrated that the use of fiberoptic bronchoscopy (FOB) as the comparator method was associated with a 22% reduction (CI 2-42%) in the diagnostic yield of SI. However, after adjustment for confounding, the meta-regression analysis showed that FOB usage (p=0.21) and saline concentration (p=0.31) were not independently associated with the diagnostic yield. SI will detect approximately three-quarters of M. tuberculosis culture-positive cases under study conditions. Significant heterogeneity in the diagnostic yield was not explained by HIV prevalence, age, or the use of FOB as the comparator method. The use of a particular nebulized saline concentration for SI cannot be recommended on the basis of this meta-regression analysis.

Safety and tolerability of sputum induction in adolescents and adults with suspected pulmonary tuberculosis.

Sputum induction by the inhalation of hypertonic saline may increase the yield of microbiological diagnosis of pulmonary tuberculosis (TB). This is particularly relevant in paucibacillary TB, such as in children or human immunodeficiency virus (HIV)-infected patients. Sputum induction must be shown to be safe and tolerable in community settings where invasive diagnostic methods are unavailable. The objective of this study was to describe the changes in physiological parameters and adverse events occurring during sputum induction in ambulatory adult and adolescent TB suspects recruited in community clinics. Sputum induction was performed in HIV-infected (n = 35) and HIV-uninfected (n = 67) TB suspects (n = 102). Oxygen saturation (%), blood pressure (mm Hg), heart rate (/minute), respiratory rate (/minute), and adverse events were monitored at baseline, continuously during the salbutamol pre-treatment and saline nebulization phases, and for 30 min afterwards. During nebulization, there was a statistically significant increase in oxygen saturation (1%, p < 0.0001), systolic BP (7 mm Hg, p < 0.0001), and diastolic BP (2 mm Hg, p = 0.008). Post-nebulization decrease in the systolic BP occurred (4 mm Hg, p = 0.016). These changes were not considered to be clinically significant. Eight minor, transitory, self-resolving adverse events occurred (labored breathing, n = 2; chest pain, n = 2; paroxysmal coughing, n = 1; elevated heart rate, n = 1; vomiting, n = 1; hypotension, n = 1), leading to procedure termination in four participants. No serious adverse events occurred. Induced sputum is safe, tolerable, and feasible in adult and adolescent TB suspects in a community healthcare setting.

The effect of new Mycobacterium tuberculosis infection on the sensitivity of prognostic TB signatures.

BACKGROUND: Tests that identify individuals at greatest risk of TB will allow more efficient targeting of preventive therapy. The WHO target product profile for such tests defines optimal sensitivity of 90% and minimum sensitivity of 75% for predicting incident TB. The CORTIS (Correlate of Risk Targeted Intervention Study) evaluated a blood transcriptomic signature (RISK11) for predicting incident TB in a high transmission setting. RISK11 is able to predict TB disease progression but optimal prognostic performance was limited to a 6-month horizon.METHODS: Using a mathematical model, we estimated how subsequent Mycobacterium tuberculosis (MTB) infection may have contributed to the decline in sensitivity of RISK11. We calculated the effect at different RISK11 thresholds (60% and 26%) and for different assumptions about the risk of MTB infection.RESULTS: Modelled sensitivity over 15 months, excluding new infection, was 28.7% (95% CI 12.3-74.1) compared to 25.0% (95% CI 12.7-45.9) observed in the trial. Modelled sensitivity exceeded the minimum criteria (>75%) over a 9-month horizon at the 60% threshold and over 12 months at the 26% threshold.CONCLUSIONS: The effect of new infection on prognostic signature performance is likely to be small. Signatures such as RISK11 may be most useful in individuals, such as household contacts, where probable time of infection is known.

Seasonal drivers of tuberculosis: evidence from over 100 years of notifications in Cape Town.

BACKGROUND: Tuberculosis incidence varies seasonally in many settings. However, the role of seasonal variation in reactivation vs. transmission is unclear.METHODS: We reviewed data on TB notifications in Cape Town, South Africa, from 1903 to 2017 (exclusive of 1995-2002, which were unavailable). Data from 2003 onward were stratified by HIV status, age and notification status (new vs. retreatment). We performed seasonal decomposition and time-dependent spectral analysis using wavelets to assess periodicity over time. We estimated monthly peak-to-peak seasonal amplitude of notifications as a percentage of the annual notification rate.RESULTS: A seasonal trend was intermittently detected between 1904 and 1994, particularly during periods of high notification rates, but was consistently and strongly evident between 2003 and 2017, with peaks in September through November, following winter. Among young children, a second, higher seasonal peak was observed in March. Seasonal variation was greater in children (<5 years, 54%, 95% CI 47-61; 5-14 years, 63%, 95% CI 58-69) than in adults (36%, 95% CI 33-39).CONCLUSIONS: Stronger seasonal effects were seen in children, in whom progression following recent infection is known to be the predominant driver of disease. These findings may support increased transmission in the winter as an important driver of TB in Cape Town.

Temporal trends in the prevalence of Mycobacterium tuberculosis infection in South African adolescents.

South Africa. 1) To measure changes in the adolescent prevalence of latent tuberculous infection (LTBI) between 2005 and 2015, and 2) to evaluate medium-term impact of TB control measures on LTBI prevalence. We compared baseline data from a cohort study (2005-2007) and a vaccine trial (2014-2015) which enrolled adolescents from the same eight South African high schools. LTBI was defined based on QuantiFERON®-TB Gold In-Tube test positivity. We analysed data from 4880 adolescents between 2005 and 2007, and 1968 adolescents between 2014 and 2015, when the average LTBI prevalence was respectively 43.8% (95%CI 28.4-59.1) vs. 48.5% (95%CI 41.1-55.8). Age-specific LTBI prevalence increased between the ages 12 and 18 years by 13% only in lower socio-economic quintile schools, where the average LTBI prevalence was unchanged between the two periods (54% vs. 53%). In the highest socio-economic quintile schools, LTBI prevalence did not increase with age; however, the average LTBI prevalence increased from 20% to 38% between the two periods. Adolescent LTBI prevalence remained high and constant over a decade, suggesting that Mycobacterium tuberculosis transmission to children was not impacted in the medium term by effective TB control efforts. Trends in adolescent LTBI prevalence should be interpreted in the context of the sociodemographic factors that affect the risk of transmission before and during adolescence. .

The effect of epinephrine by nebulization on measures of airway obstruction in patients with acute severe croup.

OBJECTIVES: To demonstrate that tests of pulmonary function applicable to sick infants and small children with acute severe viral croup would provide clear, objective evidence of responsiveness to therapy with nebulized epinephrine. STUDY DESIGN: Oesophageal pressure changes and airflows at the mouth were measured in 17 patients with acute severe croup, before and after nebulization with epinephrine. RESULTS: In 12 of the 17 patients there was a significant improvement in respiratory mechanics following epinephrine nebulization. Six of the 12 patients who responded to adrenaline also received 0.9% saline by nebulization, without improvement. No measures derived from combined flow and volume data showed any statistically significant change following epinephrine nebulization. Measures combining flow and pressure data, specifically inspiratory airway resistance, expiratory airway resistance, work of breathing, rate of work of breathing and volume for effort, showed changes of 26%, 33%, 16%, 16% and 46% respectively. The most statistically significant measures were pressure-rate product, pressure-time integral, oesophageal pressure alone and expiratory resistance. These changes persisted for at least 10 min after inhalation although there was some evidence of decline in pharmacologic effect at that time. CONCLUSIONS: Nebulized epinephrine results in a short-lived improvement in some but not all patients with croup. This reduction in respiratory effort occurs secondary to a decline in inspiratory and expiratory airway resistance. Oesophageal pressures measured via a feeding tube are satisfactory for quantification of the acute response and may be a useful continuous monitoring device. Flow measurements are unhelpful, and continuous administration of nebulized epinephrine should be investigated.

Impact of Xpert MTB/RIF rollout on management of tuberculosis in a South African community.

BACKGROUND: The Xpert MTB/RIF test shortens the time to microbiological confirmation of pulmonary tuberculosis (TB) under research conditions. OBJECTIVE: To evaluate the field impact of Xpert MTB/RIF rollout on TB diagnostic yield and time to treatment in a South African (SA) community. METHODS: We compared TB investigation outcomes for 6-month calendar periods before and after Xpert MTB/RIF rollout in a semi-rural area of SA. The proportion of adult patients who tested positive by sputum smear microscopy, liquid culture or Xpert MTB/RIF and the proportion of positive sputum smear, liquid culture or Xpert MTB/RIF tests were compared. Secondary outcomes included time to laboratory diagnosis and treatment initiation. Data were collected from the National Health Laboratory Service database and from the Western Cape Provincial Department of Health TB register. RESULTS: Regional rollout of Xpert MTB/RIF testing occurred in 2013. Of the 15 629 patients investigated in the post-rollout period, 7.9% tested positive on GeneXpert, compared with 6.4% of the 10 741 investigated in the pre-rollout period who tested positive by sputum smear microscopy (p<0.001). Median laboratory processing time was <1 day for Xpert MTB/RIF (interquartile range (IQR) 0 - 1) compared with 1 day (IQR 0 - 16) for sputum smear microscopy (p=0.001). The median time to TB treatment initiation was 4 days (IQR 2 - 8) after rollout compared with 5 days (IQR 2 - 14) before (p=0.001). CONCLUSIONS: Patients investigated for suspected pulmonary TB were more likely to be diagnosed after rollout of Xpert MTB/RIF testing, although the benefit to diagnostic yield was modest, and Xpert MTB/RIF testing was associated with a marginal improvement in time to treatment initiation.

Impact of isoniazid preventive therapy on the evaluation of long-term effectiveness of infant MVA85A vaccination.

SETTING: South Africa. OBJECTIVE: To evaluate the long-term effectiveness of infant modified vaccinia Ankara virus-expressing antigen 85A (MVA85A) vaccination against tuberculosis (TB). DESIGN: We analysed data from a double-blind randomised placebo-controlled Phase 2b MVA85A infant TB vaccine trial (2009-2012), with extended post-trial follow-up (2012-2014). Isoniazid preventive therapy (IPT) was provided by public health services according to national guidelines. The primary outcome was curative treatment for TB disease. Survival analysis and Poisson regression were used for study analysis. RESULTS: Total follow-up was 10 351 person-years of observation (pyo). Median follow-up age was 4.8 years (interquartile range 4.4-5.2). There were 328 (12%) TB cases. TB disease incidence was 3.2/100 pyo (95%CI 2.8-3.5) overall, and respectively 3.3 (95%CI 2.9-3.9) and 3.0 (95%CI 2.6-3.5)/100 pyo in the MVA85A vaccine and placebo arms. A total of 304 children (11%) received IPT, with respectively 880 and 9471 pyo among IPT and non-IPT recipients. There were 23 (7.6%) TB cases among 304 IPT recipients vs. 305 (12.9%) among 2374 non-IPT recipients (P = 0.008). IPT effectiveness was 85% (95%CI 76-91). CONCLUSION: Extended follow-up confirms no long-term effectiveness of infant MVA85A vaccination, but a six-fold reduction in TB risk can be attributed to IPT. National TB programmes in high TB burden countries should ensure optimal implementation of IPT for eligible children.

Innovative clinical trial designs to rationalize TB vaccine development.

A recent trial of a leading tuberculosis (TB) vaccine candidate in 3000 South African infants failed to show protection over that from BCG alone, and highlights the difficulties in clinical development of TB vaccines. Progression of vaccine candidates to efficacy trials against TB disease rests on demonstration of safety and immunogenicity in target populations and protection against challenge in preclinical models, but immunologic correlates of protection are unknown, and animal models may not be predictive of results in humans. Even in populations most heavily affected by TB the sample sizes required for Phase 2b efficacy trials using TB disease as an endpoint are in the thousands. Novel clinical trial models have been developed to evaluate candidate TB vaccines in selected populations using biologically relevant outcomes and innovative statistical approaches. Such proof of concept studies can be used to more rationally select vaccine candidates for advancement to large scale trials against TB disease.

A double-blind, randomised, placebo-controlled, dose-finding trial of the novel tuberculosis vaccine AERAS-402, an adenovirus-vectored fusion protein, in healthy, BCG-vaccinated infants.

BACKGROUND: Several novel tuberculosis vaccines are currently in clinical trials, including AERAS-402, an adenovector encoding a fusion protein of Mycobacterium tuberculosis antigens 85A, 85B, and TB10.4. A multicentred trial of AERAS-402 safety and immunogenicity in healthy infants was conducted in three countries in sub-Saharan Africa, using an adaptive design. METHODS: In a double-blind, randomised, placebo-controlled, dose-finding trial, we enrolled BCG-vaccinated, HIV-uninfected infants aged 16-26 weeks. Infants in the safety/dose-finding phase received two doses of AERAS-402 across three dose levels, or placebo, intramuscularly on days 0 and 28. Infants in the expanded safety phase received three doses of the highest dose level, with the 3rd dose at day 280. Follow up for safety and immunogenicity was for up to two years. RESULTS: We enrolled 206 infants (52 placebo and 154 AERAS-402 recipients) into the dose-finding phase and 281 (141 placebo and 140 AERAS-402 recipients) into the expanded safety phase. Safety data were acceptable across all dose levels. No vaccine-related deaths were recorded. A single serious adverse event of tachypnoea was deemed related to study vaccine. Antibodies directed largely against Ag85A and Ag85B were detected. Low magnitude CD4+ and CD8+ polyfunctional T cell responses were observed at all dose levels. The addition of a third dose of AERAS-402 at the highest dose level did not increase frequency or magnitude of antibody or CD8+ T cell responses. CONCLUSIONS: AERAS-402 has an acceptable safety profile in infants and was well tolerated at all dose levels. Response rate was lower than previously seen in BCG vaccinated adults, and frequency and magnitude of antigen-specific T cells were not increased by a third dose of vaccine.

Early hyperlactataemia in critically ill children.

OBJECTIVE: To examine the relationships between early hyperlactataemia, acidosis, organ failure, and mortality in children admitted to intensive care. DESIGN: Prospective observational study. Children with lactate levels > 2 mmol/l were eligible for enrolment. Post-operative patients and those with inherited metabolic disease were excluded. Seven hundred and five children admitted to intensive care were screened, and 50 children with hyperlactataemia (incidence 7%), aged 20.3 months (0.1-191) were enrolled and followed up. The Paediatric Risk of Mortality (PRISM) score, Multiorgan System Failure (MOSF) score, length of ICU stay, and outcome were recorded. Data were collected for lactate (mmol/l), pH, and base excess (BE) until 24 h after admission. Data are reported as median (range) and were analysed by the Mann-Whitney, Fisher's Exact, and Kruskal-Wallis tests, and chisquared test for trend. RESULTS: Overall mortality in the screening group was 70/705 (10%). In the study group (n = 50) median PRISM score was 19 (4-49), median MOSF score 2 (1-4), and observed mortality 32/50 (64%). Median duration of ICU stay was 6 days (2-32) in survivors, and median time until death 3 days (0-13) in nonsurvivors. Eleven nonsurvivors (34%) died within 24 h. In the screening group, hyperlactataemia on admission identified mortality with likelihood ratio = 15. In the study group, neither the admission lactate (3.8 vs 4.6 mmol/l, P = 0.27), pH (7.32 vs 7.30, P = 0.6), nor BE (-7.5 vs -8, P = 0.45) differed significantly between survivors and nonsurvivors. Neither the admission nor peak lactate increased with increasing MOSF score (P = 0.5 and 0.54). The median peak lactate level was 5 mmol/l (2-9.3) in survivors compared to 6.8 mmol/l (2.3-22) in nonsurvivors (P = 0.02), and the cumulative average lactate level was 2.4 mmol/l (1-4.9) in survivors, compared to 4.5 mmol/l (1.6-21) in nonsurvivors (P = 0.0003). Persistent hyperlactataemia 24 h after admission identified mortality with likelihood ratio = 7. CONCLUSION: Hyperlactataemia on admission to intensive care is associated with a high mortality in children. Nonsurvivors within this group may be distinguished by the peak lactate level, or by persistent hyperlactataemia after 24 h of treatment.

Are transoesophageal Doppler parameters a reliable guide to paediatric haemodynamic status and fluid management?

OBJECTIVE: Transoesophageal Doppler (TOD) has been used in adults to optimise left ventricular filling on the basis of the waveform parameters. We wished to see if a similar relationship exists in children, specifically: (a) whether change in thermodilution stroke volume (SV) following a fluid bolus corresponded to change in Doppler stroke distance, Doppler corrected flow time (FTc), or central venous pressure (CVP); (b) whether a response to fluid challenge (defined as an increase in SV of greater than 10%) can be predicted on the basis of an absolute value for FTc or CVP prior to fluid bolus; and (c) the relationship between FTc and systemic vascular resistance index. DESIGN: Prospective, comparison study. SETTING: Sixteen-bed paediatric intensive care unit of a university hospital. PATIENTS: Ninety-four ventilated children were studied, median (range) age 25 months (4 days- 16 years). Diagnoses included: post-cardiac surgery (n = 58), sepsis/multi-organ failure (n = 29), respiratory disease (n = 5), and other (n = 2). INTERVENTIONS: A 4-MHz, 5.5-mm diameter, flexible TOD probe was placed when patients were haemodynamically stable. Five consecutive measurements of stroke distance and FTc were made and averaged, concurrently with five SV measurements by femoral artery thermodilution. SV was then augmented by administration of fluid (10 ml/kg), and haemodynamic recordings were repeated. MEASUREMENTS AND MAIN RESULTS: The median (range) SV was 17 ml (2-64 ml). The median coefficients of variation were 3.9 % for SV, 3.5 % for stroke distance, and 3.1% for FTc. Changes in SV were accurately tracked by changes in stroke distance (mean bias 1.8 %, limits of agreement +/- 17%), but not by FTc or CVP. FTc was weakly inversely correlated with systemic vascular resistance (r = -0.15, P < 0.05). Among non-cardiac patients (n = 36), the optimal FTc that predicted an improvement in SV following fluid bolus was 0.394 s (area under ROC curve 0.756), giving a sensitivity of 90 %, specificity of 62 %, positive predictive value of 47 %, and a negative predictive value of 94 %. CVP was a poor predictor for all patient groups. CONCLUSIONS: TOD stroke distance is able to follow changes in SV following fluid bolus amongst ventilated children, and can predict when further volume loading is unlikely to improve SV amongst general, but not cardiac ICU patients. CVP is a poor discriminator of volume status in this group of patients.

Evaluation of the 5-French saline paediatric gastric tonometer.

OBJECTIVE: To evaluate the paediatric 5-French (Fr) saline-filled gastric tonometer. DESIGN: (a) In vitro comparison of saline bath reference pCO2 with tonometric pCO2 measured by normal saline-filled and phosphate-buffered saline-filled 5-Fr tonometers, and by a recirculating gas tonometer. ( b) In vivo comparison of gastric intramucosal pCO2i, measured by normal saline-filled 5-Fr tonometer (NST) and simultaneously by recirculating gas tonometer (RGT) in ten paediatric intensive care patients. (c) In vivo comparison of pCO2i measured simultaneously by 2 NST 5-Fr tonometers, before and after enteral feeding, in ten paediatric intensive care patients. MEASUREMENTS AND MAIN RESULTS: (a) Twenty consecutive measurements of pCO2 were made at constant reference pCO2 of 19, 38, 56, and 75 mmHg (2.5, 5.0, 7.5, and 10.0 kPa), respectively. The NST tonometer underestimated reference pCO2 by mean bias (limits of agreement) of 58% (20%), and the phosphate-buffered saline-filled tonometer by 6% (26%). The RGT showed mean bias 5.7% with narrow limits of agreement (1.5%). (b) In 50 paired (NST vs. RGT) in vivo measurements over pCO2i range 23-73 mmHg (3.0-9.7 kPa), the NST underestimated RGT pCO2i by a mean bias of 10 mmHg (1.3 kPa), with limits of agreement +/-10 mmHg (1.5 kPa). This resulted in NST consistently overestimating pHi and underestimating pCO2 gap (both P < 0.001). (c) One hundred simultaneous paired NST measurements were assessed (50 without, and 50 with enteral feeding). The mean biases (limits of agreement) were identical in the fasted and fed states 0.4+/-6 mmHg, with no difference between the fed and fasting states (P = 0.7). CONCLUSIONS: There are inherent problems in the methodology of saline tonometry, which adversely affect the accuracy and reliability of the 5-Fr paediatric gastric tonometer in comparison to recirculating gas tonometry.

Clinical validation of cardiac output measurements using femoral artery thermodilution with direct Fick in ventilated children and infants.

OBJECTIVE: To validate clinically cardiac output (CO) measurements using femoral artery thermodilution in ventilated children and infants by comparison with CO estimated from the Fick equation via a metabolic monitor. DESIGN: Prospective, comparison study. SETTING: Paediatric intensive care unit of a university hospital. PATIENTS: 24 ventilated infants and children, aged 0.3 to 175 months (median age 19 months). INTERVENTIONS: Oxygen consumption measurements were made and averaged over a 5-min period, at the end of which arterial and mixed venous blood samples were taken and oxygen saturations measured by co-oximetry, with CO being calculated using the Fick equation. Over this 5-min period, five sets of femoral arterial thermodilution (FATD) measurements were made and averaged. One comparison of CO values was made per patient. RESULTS: Mean Fick CO was 2.55 l/min (range 0.24 to 8.71 l/min) and mean FATD CO was 2.51 l/min (range 0.28-7.96 l/min). The mean bias was 0.03 l/min (95% confidence interval -0.07 to 0.14 l/min), with limits of agreement of -0.45 to 0.52 l/min. When indexed to body surface area, the mean Fick cardiac index became 3.51 l/min per m2 (1.52-6.98 l/min per m2) and mean FATD 3.49 l/min per m2 (1.74-6.84 l/min per m2). The mean bias was 0.02 l/min per m2 (95% confidence interval -0.11 to 0.15 l/min per m2) with limits of agreement of-0.57 to 0.61 l/min per m2. The mean FATD coefficient of variation was 5.8% (SEM 0.5%). CONCLUSIONS: FATD compares favourably with Fick derived CO estimates in infants and children and may represent an advance in haemodynamic monitoring of critically ill children.

HIV infection of undetermined origin during infancy.

The case histories of two children with horizontally acquired HIV infection are described. These children were diagnosed at a paediatric hospital in sub-Saharan Africa. Although the source(s) of infection was not identified, both children had had several contacts with the health service, experienced invasive procedures and ingested expressed milk from their own mothers during hospital admission. Health-care institutions, particularly those located in high HIV prevalence areas, must implement effective infection control measures to ensure that the risk of horizontal infection is minimized. Attention should be given to practices that are unique to each clinical discipline.

Analysis of time to regulatory and ethical approval of SATVI TB vaccine trials in South Africa.

BACKGROUND: Tuberculosis (TB) vaccine trials in South Africa must be approved by the Medicines Control Council (MCC) and by a human research ethics committee (HREC). Delays in regulatory and ethical approval may affect operational and budget planning and clinical development of the product. AIM: Our aim was to analyse the time to regulatory and ethical approval for TB vaccine trials conducted by the South African Tuberculosis Vaccine Initiative (SATVI) and to evaluate factors that influence time to final approval. METHOD: Sixteen new TB vaccine clinical trials conducted by SATVI between 2004 and 2012 on infants, children, and adults were included. The period between submission and final approval was determined for protocols submitted to the MCC and the University of Cape Town HREC. RESULTS: Median approval time following first submission to the MCC was 122 days (IQR 112 - 168; range 71 - 350), and for protocol amendments 103 days (interquartile range (IQR) 76 - 141; range 23 - 191; n=30). Median time following first submission for HREC approval was 60 days (IQR 33 - 81; range 18 - 125), and for amendments 6 days (IQR 4 - 13; range 1 - 37; n=30). There was no significant difference in approval time by trial phase, year of submission, revisions required, study population, sample size, or whether a clinical research organisation (CRO) was used. CONCLUSION: The time needed for regulatory and ethics approval was highly variable, but MCC approval for first submissions took twice as long as HREC approval and was the primary determinant of time to final approval. National regulatory capacity should be strengthened to facilitate the conduct of new TB vaccine trials in this country with its high burden of TB.

Vaccine trials in the developing world: operational lessons learnt from a phase IV poliomyelitis vaccine trial in South Africa.

BACKGROUND: Conducting vaccine trials in developing nations is necessary but operationally complex. We describe operational lessons learnt from a phase IV poliomyelitis vaccine trial in a semi-rural region of South Africa. METHODS: We reviewed operational data collected over the duration of the trial with respect to staff recruitment and training, participant recruitment and retention, and cold chain maintenance. RESULTS-LESSONS LEARNT: The recruitment model we used that relied on the 24h physical presence of a team member in the birthing unit was expensive and challenging to manage. Forecasting of enrolment rates was complicated by incomplete baseline data and by the linear nature of forecasts that do not take into account changing variables. We found that analyzing key operational data to monitor progress of the trial enabled us to identify problem areas timeously, and to facilitate a collegial problem-solving process by the extended trial team. Pro-actively nurturing a working relationship with the public sector health care system and the community was critical to our success. Despite the wide geographical area and lack of fixed addresses, we maintained an excellent retention rate through community assistance and the use of descriptive residential information. Training needs of team members were ongoing and dynamic and we discovered that these needs that were best met by an in-house, targeted and systemized training programme. The use of vaccine refrigerators instead of standard frost-free refrigerators is cost-effective and necessary to maintain the cold-chain. CONCLUSION: Operational challenges of a vaccine trial in developing world populations include inexperienced staff, the close liaison required between researchers and public health care services, impoverished participants that require complex recruitment and retention strategies, and challenges of distance and access. These challenges can be overcome by innovative strategies that allow for the unique characteristics of the setting, trial population, and trial team.

Tuberculosis case finding for vaccine trials in young children in high-incidence settings: a randomised trial.

SETTING: A high tuberculosis (TB) burden rural area in South Africa. OBJECTIVE: To compare TB case yield and disease profile among bacille Calmette-Guérin (BCG) vaccinated children using two case-finding strategies from birth until 2 years of age. DESIGN: BCG-vaccinated infants were enrolled within 2 weeks of birth and randomised to 3-monthly home visits for questionnaire-based TB screening plus record surveillance of TB registers, hospital admission and X-ray lists at health facilities for TB suspects and cases (Group 1), or record surveillance (as above) only (Group 2). Both groups received a close-out visit after 2 years. Participants were evaluated for suspected TB disease using standardised investigations. RESULTS: A total of 4786 infants were enrolled: 2392 were randomised to Group 1 and 2394 to Group 2. The case-finding rate was significantly greater in Group 1 (2.2/100 py) than in Group 2 (0.8/100 py), with a case-finding rate ratio of 2.6 (95%CI 1.8-4.0, P < 0.001). Although the proportion of cases with bacteriological confirmation was lower in Group 1, this difference did not reach statistical significance. There was also no significant difference in the proportions with TB symptoms and signs. CONCLUSION: Home visits combined with record surveillance detected significantly more cases than record surveillance with a single study-end visit. The TB case profile did not differ significantly between the two groups.