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1.  Pneumocystis pneumonia in South African children diagnosed by molecular methods 
BMC Research Notes  2014;7:26.
Background
Pneumocystis pneumonia (PCP) is an important cause of hospitalization and mortality in HIV-infected children. However, the incidence of PCP has been underestimated due to poor sensitivity of diagnostic tests. The use of polymerase chain reaction (PCR) for pneumocystis has enabled more reliable diagnosis. This study describes the incidence, clinical features and outcome of PCP in South African children diagnosed using PCR.
Methods
A prospective study of children hospitalised in South Africa with suspected PCP was done from November 2006 to August 2008. Clinical, laboratory and radiological information were collected. Lower respiratory tract specimens were obtained for PCP immunofluorescence (IF), real- time PCR for pneumocystis, bacterial and mycobacterial culture. Nasopharyngeal aspirates were taken for immunofluorescence (IF), real-time PCR for pneumocystis and PCR for respiratory viruses. A blood specimen for bacterial culture and for cytomegalovirus PCR was taken. Children were followed for the duration of their hospitalisation and the outcome was recorded.
Results
202 children [median (interquartile range, IQR) age 3.2 (2.1– 4.6) months] were enrolled; 124 (61.4%) were HIV infected. PCP was identified in 109 (54%) children using PCR, compared to 43 (21%) using IF and Grocott staining (p < 0.0001). Most PCP cases (88, 81%) occurred in HIV-infected children. All 21 cases (19%) occurring in HIV- negative children had another risk factor for PCP. On logistic regression, predictive factors for PCP were HIV infection, lack of fever, high respiratory rate and low oxygen saturation whilst cotrimoxazole prophylaxis was protective (OR 0.24; 95% CI 0.1 to 0.5; p < 0.002). The case fatality of children with PCP was higher than those without PCP (32.1% versus 17.2%; relative risk 1.87; 95% confidence interval (CI) 1.11 – 3.15). Amongst HIV-infected children, a CD4 less than 15% was the only independent predictor of mortality.
Conclusions
The diagnostic yield for PCP is more than 2.5 times higher on PCR than other detection methods. PCP is a very common cause of severe hypoxic pneumonia and is associated with high mortality in HIV-infected African infants.
doi:10.1186/1756-0500-7-26
PMCID: PMC3892044  PMID: 24410938
Pneumocystis pneumonia; HIV; Children; Prophylaxis; PCR; Diagnosis; Incidence
2.  Antibiotic Stewardship Ward Rounds and a Dedicated Prescription Chart Reduce Antibiotic Consumption and Pharmacy Costs without Affecting Inpatient Mortality or Re-Admission Rates 
PLoS ONE  2013;8(12):e79747.
Background
Antibiotic consumption is a major driver of bacterial resistance. To address the increasing burden of multi-drug resistant bacterial infections, antibiotic stewardship programmes are promoted worldwide to rationalize antibiotic prescribing and conserve remaining antibiotics. Few studies have been reported from developing countries and none from Africa that report on an intervention based approach with outcomes that include morbidity and mortality.
Methods
An antibiotic prescription chart and weekly antibiotic stewardship ward round was introduced into two medical wards of an academic teaching hospital in South Africa between January-December 2012. Electronic pharmacy records were used to collect the volume and cost of antibiotics used, the patient database was analysed to determine inpatient mortality and 30-day re-admission rates, and laboratory records to determine use of infection-related tests. Outcomes were compared to a control period, January-December 2011.
Results
During the intervention period, 475.8 defined daily doses were prescribed per 1000 inpatient days compared to 592.0 defined daily doses/1000 inpatient days during the control period. This represents a 19.6% decrease in volume with a cost reduction of 35% of the pharmacy’s antibiotic budget. There was a concomitant increase in laboratory tests driven by requests for procalcitonin. There was no difference in inpatient mortality or 30-day readmission rate during the control and intervention periods.
Conclusions
Introduction of antibiotic stewardship ward rounds and a dedicated prescription chart in a developing country setting can achieve reduction in antibiotic consumption without harm to patients. Increased laboratory costs should be anticipated when introducing an antibiotic stewardship program.
doi:10.1371/journal.pone.0079747
PMCID: PMC3857167  PMID: 24348995
3.  Epidemiology of Staphylococcus aureus Bacteraemia at a Tertiary Children’s Hospital in Cape Town, South Africa 
PLoS ONE  2013;8(10):e78396.
Background
Staphylococcus aureus is an important pathogen in paediatric patients with bloodstream infections. The epidemiology of S. aureus bacteraemia, however, has not been well documented in children in South Africa.
Methods
A retrospective study was conducted at a children’s hospital in Cape Town, South Africa, to investigate the epidemiology of S. aureus bacteraemia from 2007-2011. The incidence, clinical presentation, risk factors, management and outcomes of methicillin sensitive S. aureus (MSSA) and methicillin resistant S. aureus (MRSA) bacteraemia were compared.
Results
Over the five year study period, 365 episodes of S. aureus bacteraemia were identified. The annual incidence was 3.28 cases per 1000 hospital admissions. MRSA was responsible for 26% of S. aureus bacteraemia and 72% of nosocomial infections. Only six possible cases of community-acquired MRSA infections were described. MSSA bacteraemia was more likely to present as pulmonary and bone or joint infections, while bacteraemia without a source was the most common presentation with MRSA.  Infants, children with malnutrition, and residents of long-term care facilities were at highest risk for MRSA bacteraemia. The overall case fatality rate for S. aureus bacteraemia was 8.8% over five years, with MRSA being the only significant risk factor for mortality.
Conclusion
The incidence of S. aureus bacteraemia and MRSA bacteraemia in children has remained stable over the past five years. MRSA is a predominantly nosocomial pathogen in children with S. aureus bacteraemia in Cape Town, South Africa.
doi:10.1371/journal.pone.0078396
PMCID: PMC3805599  PMID: 24167621
4.  ICU-Associated Acinetobacter baumannii Colonisation/Infection in a High HIV-Prevalence Resource-Poor Setting 
PLoS ONE  2012;7(12):e52452.
Background
There are hardly any data about the incidence, risk factors and outcomes of ICU-associated A.baumannii colonisation/infection in HIV-infected and uninfected persons from resource-poor settings like Africa.
Methods
We reviewed the case records of patients with A.baumannii colonisation/infection admitted into the adult respiratory and surgical ICUs in Cape Town, South Africa, from January 1 to December 31 2008. In contrast to colonisation, infection was defined as isolation of A.baumannii from any biological site in conjunction with a compatible clinical picture warranting treatment with antibiotics effective against A.baumannii.
Results
The incidence of A.baumannii colonisation/infection in 268 patients was 15 per 100 person-years, with an in-ICU mortality of 26.5 per 100 person-years. The average length of stay in ICU was 15 days (range 1–150). A.baumannii was most commonly isolated from the respiratory tract followed by the bloodstream. Independent predictors of mortality included older age (p = 0.02), low CD4 count if HIV-infected (p = 0.038), surgical intervention (p = 0.047), co-morbid Gram-negative sepsis (p = 0.01), high APACHE-II score (p = 0.001), multi-organ dysfunction syndrome (p = 0.012), and a positive blood culture for A.baumannii (p = 0.017). Of 21 A.baumannii colonised/infected HIV-positive persons those with clinical AIDS (CD4<200 cells/mm3) had significantly higher in-ICU mortality and were more likely to have a positive blood culture.
Conclusion In this resource-poor setting A.baumannii infection in critically ill patients is common and associated with high mortality. HIV co-infected patients with advanced immunosuppression are at higher risk of death.
doi:10.1371/journal.pone.0052452
PMCID: PMC3531465  PMID: 23300673
5.  Genetic basis of rifampicin resistance in methicillin-resistant Staphylococcus aureus suggests clonal expansion in hospitals in Cape Town, South Africa 
BMC Microbiology  2012;12:46.
Background
Since 2001, several studies have reported high rifampicin resistance rates (45 - 100%) among methicillin-resistant Staphylococcus aureus (MRSA) isolates from South Africa. The authors previously characterised 100 MRSA isolates from hospitals in Cape Town, South Africa; forty-five percent of these isolates were rifampicin-resistant. The majority (44/45) corresponded to ST612-MRSA-IV, which is prevalent in South Africa, but has not been reported frequently elsewhere. The remaining rifampicin-resistant isolate corresponded to ST5-MRSA-I. The aim of this study was to investigate further the prevalence and genetic basis of rifampicin-resistance in MRSA isolates from hospitals in Cape Town.
Results
Between July 2007 and June 2011, the prevalence of rifampicin-resistant MRSA in hospitals in Cape Town ranged from 39.7% to 46.4%. Based on the results of the aforementioned study, nine ST612-MRSA-IV isolates, the rifampicin-resistant ST5-MRSA-I isolate, and two rifampicin-susceptible MRSA isolates were investigated. Four previously described ST612-MRSA-IV isolates, including two each from South Africa and Australia, were also included.
The ST5-MRSA-I isolate carried a single mutational change, H481Y, commonly associated with high-level rifampicin resistance. All ST612-MRSA-IV isolates carried an uncommon double amino acid substitution in RpoB, H481N, I527M, whilst one of the Australian ST612-MRSA-IV isolates carried an additional mutation within rpoB, representing a novel rpoB genotype: H481N, I527M, K579R. All ST612-MRSA-IV isolates also shared a unique silent single nucleotide polymorphism (SNP) within rpoB.
Conclusions
That local ST612-MRSA-IV isolates described here share an uncommon rpoB genotype and a unique silent SNP suggests this clone may have undergone clonal expansion in hospitals in Cape Town. Further, the data suggest that these isolates may be related to rifampicin-resistant ST612-MRSA-IV previously described in South Africa and Australia.
doi:10.1186/1471-2180-12-46
PMCID: PMC3364154  PMID: 22448673
6.  Characteristics and Early Outcomes of Patients With Xpert MTB/RIF-Negative Pulmonary Tuberculosis Diagnosed During Screening Before Antiretroviral Therapy 
Comparison of the characteristics of HIV-infected patients with Xpert-positive and Xpert-negative tuberculosis and relationship of Xpert status with subsequent clinical and programmatic outcomes.
Background. A proportion of patients with tuberculosis diagnosed by sputum culture during screening before antiretroviral therapy (ART) have false-negative Xpert MTB/RIF assay results (Xpert-negative tuberculosis). We determined the characteristics and early ART program outcomes of such patients.
Methods. Adult patients who enrolled in a South African township ART service were systematically screened for pulmonary tuberculosis regardless of symptoms by testing paired sputum samples with Xpert MTB/RIF and liquid culture. The ART service provided follow-up for all patients, and early (90-day) programmatic outcomes were determined.
Results. Among 602 patients screened, 523 had ≥1 Xpert and culture result, yielding 89 culture-positive tuberculosis diagnoses. Of these, 37 (42%) of the patients with tuberculosis were Xpert-negative when a single sputum sample was tested, compared with 25 (28%) when 2 samples were tested. Compared with patients with Xpert-positive tuberculosis, those with Xpert-negative tuberculosis (using either definition) had substantially higher CD4 cell counts, lower plasma viral loads, higher hemoglobin concentrations, and higher body mass index. Their tuberculosis was also less advanced, with a lower frequency of prolonged cough (≥2 weeks), less extensive radiographic abnormalities, and a lower frequency of detectable lipoarabinomannan antigenuria and mycobacteriuria. Xpert-negative cases were all sputum smear negative with prolonged time to culture positivity (median, 21 days). Despite greater delays in starting tuberculosis treatment, Xpert-negative patients were less likely to die during follow-up.
Conclusions. Compared to patients with Xpert-positive tuberculosis diagnosed during pre-ART screening, Xpert-negative cases had less advanced immunosuppression and less advanced tuberculosis and did not have adverse outcomes despite substantial delays in starting tuberculosis treatment.
doi:10.1093/cid/cir1039
PMCID: PMC3309885  PMID: 22318975
7.  Comparison of Quantitative Techniques including Xpert MTB/RIF to Evaluate Mycobacterial Burden 
PLoS ONE  2011;6(12):e28815.
Introduction
Accurate quantification of mycobacterial load is important for the evaluation of patient infectiousness, disease severity and monitoring treatment response in human and in-vitro laboratory models of disease. We hypothesized that newer techniques would perform as well as solid media culture to quantify mycobacterial burden in laboratory specimens.
Methods
We compared the turn-around-time, detection-threshold, dynamic range, reproducibility, relative discriminative ability, of 4 mycobacterial load determination techniques: automated liquid culture (BACTEC-MGIT-960), [3H]-uracil incorporation assays, luciferase-reporter construct bioluminescence, and quantitative PCR(Xpert -MTB/RIF) using serial dilutions of Mycobacterium bovis and Mycobacterium tuberculosis H37RV. Mycobacterial colony-forming-units(CFU) using 7H10-Middlebrook solid media served as the reference standard.
Results
All 4 assays correlated well with the reference standard, however, bioluminescence and uracil assays had a detection threshold ≥1×103 organisms. By contrast, BACTEC-MGIT-960 liquid culture, although only providing results in days, was user-friendly, had the lowest detection threshold (<10 organisms), the greatest discriminative ability (1 vs. 10 organisms; p = 0.02), and the best reproducibility (coefficient of variance of 2% vs. 38% compared to uracil incorporation; p = 0.02). Xpert-MTB/RIF correlated well with mycobacterial load, had a rapid turn-around-time (<2 hours), was user friendly, but had a detection limit of ∼100 organisms.
Conclusions
Choosing a technique to quantify mycobacterial burden for laboratory or clinical research depends on availability of resources and the question being addressed. Automated liquid culture has good discriminative ability and low detection threshold but results are only obtained in days. Xpert MTB/RIF provides rapid quantification of mycobacterial burden, but has a poorer discrimination and detection threshold.
doi:10.1371/journal.pone.0028815
PMCID: PMC3245241  PMID: 22216117
8.  Improved detection of Pneumocystis jirovecii in upper and lower respiratory tract specimens from children with suspected pneumocystis pneumonia using real-time PCR: a prospective study 
BMC Infectious Diseases  2011;11:329.
Background
Pneumocystis pneumonia (PCP) is a major cause of hospitalization and mortality in HIV-infected African children. Microbiologic diagnosis relies predominantly on silver or immunofluorescent staining of a lower respiratory tract (LRT) specimens which are difficult to obtain in children. Diagnosis on upper respiratory tract (URT) specimens using PCR has been reported useful in adults, but data in children are limited. The main objectives of the study was (1) to compare the diagnostic yield of PCR with immunofluorescence (IF) and (2) to investigate the usefulness of upper compared to lower respiratory tract samples for diagnosing PCP in children.
Methods
Children hospitalised at an academic hospital with suspected PCP were prospectively enrolled. An upper respiratory sample (nasopharyngeal aspirate, NPA) and a lower respiratory sample (induced sputum, IS or bronchoalveolar lavage, BAL) were submitted for real-time PCR and direct IF for the detection of Pneumocystis jirovecii. A control group of children with viral lower respiratory tract infections were investigated with PCR for PCP.
Results
202 children (median age 3.3 [inter-quartile range, IQR 2.2 - 4.6] months) were enrolled. The overall detection rate by PCR was higher than by IF [180/349 (52%) vs. 26/349 (7%) respectively; p < 0.0001]. PCR detected more infections compared to IF in lower respiratory tract samples [93/166 (56%) vs. 22/166 (13%); p < 0.0001] and in NPAs [87/183 (48%) vs. 4/183 (2%); p < 0.0001]. Detection rates by PCR on upper (87/183; 48%) compared with lower respiratory tract samples (93/166; 56%) were similar (OR, 0.71; 95% CI, 0.46 - 1.11). Only 2/30 (6.6%) controls were PCR positive.
Conclusion
Real-time PCR is more sensitive than IF for the detection of P. jirovecii in children with PCP. NPA samples may be used for diagnostic purposes when PCR is utilised. Wider implementation of PCR on NPA samples is warranted for diagnosing PCP in children.
doi:10.1186/1471-2334-11-329
PMCID: PMC3254081  PMID: 22123076
9.  Rapid Diagnosis of Tuberculosis with the Xpert MTB/RIF Assay in High Burden Countries: A Cost-Effectiveness Analysis 
PLoS Medicine  2011;8(11):e1001120.
A cost-effectiveness study by Frank Cobelens and colleagues reveals that Xpert MTB/RIF is a cost-effective method of tuberculosis diagnosis that is suitable for use in low- and middle-income settings.
Background
Xpert MTB/RIF (Xpert) is a promising new rapid diagnostic technology for tuberculosis (TB) that has characteristics that suggest large-scale roll-out. However, because the test is expensive, there are concerns among TB program managers and policy makers regarding its affordability for low- and middle-income settings.
Methods and Findings
We estimate the impact of the introduction of Xpert on the costs and cost-effectiveness of TB care using decision analytic modelling, comparing the introduction of Xpert to a base case of smear microscopy and clinical diagnosis in India, South Africa, and Uganda. The introduction of Xpert increases TB case finding in all three settings; from 72%–85% to 95%–99% of the cohort of individuals with suspected TB, compared to the base case. Diagnostic costs (including the costs of testing all individuals with suspected TB) also increase: from US$28–US$49 to US$133–US$146 and US$137–US$151 per TB case detected when Xpert is used “in addition to” and “as a replacement of” smear microscopy, respectively. The incremental cost effectiveness ratios (ICERs) for using Xpert “in addition to” smear microscopy, compared to the base case, range from US$41–$110 per disability adjusted life year (DALY) averted. Likewise the ICERS for using Xpert “as a replacement of” smear microscopy range from US$52–$138 per DALY averted. These ICERs are below the World Health Organization (WHO) willingness to pay threshold.
Conclusions
Our results suggest that Xpert is a cost-effective method of TB diagnosis, compared to a base case of smear microscopy and clinical diagnosis of smear-negative TB in low- and middle-income settings where, with its ability to substantially increase case finding, it has important potential for improving TB diagnosis and control. The extent of cost-effectiveness gain to TB programmes from deploying Xpert is primarily dependent on current TB diagnostic practices. Further work is required during scale-up to validate these findings.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Tuberculosis (TB) is a bacterial disease that infects one-third of the world's population. The disease is caused by Mycobacterium tuberculosis, a bacterium that most commonly infects the lungs (known as pulmonary TB) and is transmitted from person to person when an infected individual coughs, sneezes, or talks. The symptoms of TB include chest pain, weight loss, fever, and a persistent cough that sometimes contains blood. Only 5%–10% of people who are infected with TB become sick or infectious, but people with weakened immune systems, such as individuals who are HIV-positive, are more likely to develop the disease. TB is estimated to have killed 1.7 million people in 2009 and is currently the leading cause of death among people infected with HIV.
Why Was This Study Done?
Although TB can be treated with a six-month course of antibiotics, effectively diagnosing TB is not always straightforward and drug resistance is becoming an increasing problem. One of the most common and simple methods to diagnose TB is a technique called sputum smear microscopy, which involves examining matter from the lungs under a microscope for the presence of TB-causing bacteria. However, despite being cheap and relatively simple, the test does not always detect active TB (smear-negative) and cannot determine whether the TB-causing bacteria are resistant to antibiotics. The World Health Organization has recently endorsed a new rapid test, called Xpert MTB/RIF (referred to as Xpert), for the initial diagnosis of TB. The test uses DNA amplification methods to reliably and quickly detect TB and whether infecting bacteria are resistant to the antibiotic rifampicin. The new test is expensive so there are concerns that the test might not be cost-effective in low- and middle-income countries.
What Did the Researchers Do and Find?
The researchers used a technique called modeling to simulate the outcome of 10,000 individuals with suspected TB as they went through a hypothetical diagnostic and treatment pathway. The model compared the costs associated with the introduction of Xpert to a base case for two different scenarios. In the base case all individuals with suspected TB had two sputum smear microscopy examinations followed by clinical diagnosis if they were smear-negative. For the different scenarios Xpert was either used in addition to the two sputum smear microscopy examinations (if the patient was smear-negative) or Xpert was used as a replacement for sputum smear microscopy for all patients. Different input parameters, based on country-specific estimates, were applied so that the model reflected the implementation of Xpert in India, South Africa, and Uganda.
In the researcher's model the introduction of Xpert increased the proportion of TB-infected patients who were correctly diagnosed with TB in any of the settings. However, the cost per TB case detected increased by approximately US$100 in both scenarios. Although the cost of detection increased significantly, the cost of treatment increased only moderately because the number of false-positive cases was reduced. For example, the percentage of treatment costs spent on false-positive diagnoses in India was predicted to fall from 22% to 4% when Xpert was used to replace sputum smear microscopy. The model was used to calculate incremental cost effectiveness ratios (ICERs—the additional cost of each disability-adjusted life year [DALY] averted) for the different scenarios of Xpert implementation in the different settings. In comparison to the base case, introducing Xpert in addition to sputum smear microscopy produced ICERs ranging from US$41 to US$110 per DALY averted, while introducing Xpert instead of sputum smear microscopy yielded ICERs ranging from US$52 to US$138 per DALY averted.
What Do These Findings Mean?
The findings suggest that the implementation of Xpert in addition to, or instead of, sputum smear microscopy will be cost-effective in low- and middle-income countries. The calculated ICERs are below the World Health Organization's “willingness to pay threshold” for all settings. That is the incremental cost of each DALY averted by introduction of Xpert is below the gross domestic product per capita for each country ($1,134 for India, $5,786 South Africa, and $490 for Uganda in 2010). However, the authors note that achieving ICERs below the “willingness to pay threshold” does not necessarily mean that countries have the resources to implement the test. The researchers also note that there are limitations to their study; additional unknown costs associated with the scale-up of Xpert and some parameters, such as patient costs, were not included in the model. Although the model strongly suggests that Xpert will be cost-effective, the researchers caution that initial roll-out of Xpert should be carefully monitored and evaluated before full scale-up.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001120.
The World Health Organization provides information on all aspects of tuberculosis, including tuberculosis diagnostics and the Stop TB Partnership (some information is in several languages)
The US Centers for Disease Control and Prevention has information about tuberculosis, including information on the diagnosis of tuberculosis disease
MedlinePlus has links to further information about tuberculosis (in English and Spanish)
doi:10.1371/journal.pmed.1001120
PMCID: PMC3210757  PMID: 22087078
10.  Antiretroviral Program Associated with Reduction in Untreated Prevalent Tuberculosis in a South African Township 
Rationale: In 2005, we reported high prevalence of untreated pulmonary tuberculosis (TB) in a South African community. Prevalent untreated TB is the main source of transmission. In settings with large burdens of human immunodeficiency virus (HIV) and TB, highly active antiretroviral therapy (HAART) may contribute to TB control.
Objectives: To assess the community-level impact of HAART on TB prevalence, we repeated a community-based TB prevalence cross-sectional survey in 2008 following HAART roll-out.
Methods: A random 10% adult population sample was identified from the community. Participants provided two sputum specimens for acid-fast bacilli microscopy and TB culture. Oral transudate specimen was collected for anonymous HIV testing, linked to TB diagnosis. An interviewer-administered, structured questionnaire identified TB and HIV history and risk factors.
Measurements and Main Results: In the 2008 survey, 1,250 adults participated (90% response rate); 306 (25%) tested HIV positive, of which 60 (20%) were receiving HAART. A total of 20 TB cases were identified (12 receiving TB treatment), representing a significant decline in prevalence from 3.2 to 1.6% (P = 0.02) between the surveys. TB prevalence in participants not infected with HIV was unchanged (P = 0.90). The decline occurred among participants not infected with HIV, decreasing from 9.2 to 3.6% in 2005 to 2008, respectively (P = 0.003). In participants infected with HIV, prevalence of treated TB declined from 4 to 2.3% (P = 0.06), and untreated TB prevalence from 5.2 to 1.3% (P = 0.02). The proportion of untreated TB in patients receiving HAART decreased significantly, from 22 to 0% (P < 0.001).
Conclusions: Prevalence of undiagnosed TB declined significantly over a period of increasing HAART availability. The decline was predominantly in individuals infected with HIV receiving HAART.
doi:10.1164/rccm.201004-0598OC
PMCID: PMC2970849  PMID: 20558626
tuberculosis; prevalence; human immunodeficiency virus; antiretroviral therapy
11.  Screening for HIV-Associated Tuberculosis and Rifampicin Resistance before Antiretroviral Therapy Using the Xpert MTB/RIF Assay: A Prospective Study 
PLoS Medicine  2011;8(7):e1001067.
In a prospective study, Stephen Lawn and colleagues find that pre-ART screening with Xpert MTB/RIF increased tuberculosis case detection by 45% compared to smear microscopy in HIV-positive patients at high risk of TB risk. AE competing interests must also pull through to the proof. “The Academic Editor, Madhukar Pai, declares that he consults for the Bill & Melinda Gates Foundation (BMGF). The BMGF supported FIND which was involved in the development of the Xpert MTB/RIF assay. He also co-chairs the Stop TB Partnership's New Diagnostics Working Group that was involved in the WHO endorsement of the Xpert assay.” Linked: Scott pmed.1001061; Evans pmed.1001064; Dowdy pmed.1001063
Background
The World Health Organization has endorsed the Xpert MTB/RIF assay for investigation of patients suspected of having tuberculosis (TB). However, its utility for routine TB screening and detection of rifampicin resistance among HIV-infected patients with advanced immunodeficiency enrolling in antiretroviral therapy (ART) services is unknown.
Methods and Findings
Consecutive adult HIV-infected patients with no current TB diagnosis enrolling in an ART clinic in a South African township were recruited regardless of symptoms. They were clinically characterised and invited to provide two sputum samples at a single visit. The accuracy of the Xpert MTB/RIF assay for diagnosing TB and drug resistance was assessed in comparison with other tests, including fluorescence smear microscopy and automated liquid culture (gold standard) and drug susceptibility testing. Of 515 patients enrolled, 468 patients (median CD4 cell count, 171 cells/µl; interquartile range, 102–236) produced at least one sputum sample, yielding complete sets of results from 839 samples. Mycobacterium tuberculosis was cultured from 81 patients (TB prevalence, 17.3%). The overall sensitivity of the Xpert MTB/RIF assay for culture-positive TB was 73.3% (specificity, 99.2%) compared to 28.0% (specificity, 100%) using smear microscopy. All smear-positive, culture-positive disease was detected by Xpert MTB/RIF from a single sample (sensitivity, 100%), whereas the sensitivity for smear-negative, culture-positive TB was 43.4% from one sputum sample and 62.3% from two samples. Xpert correctly identified rifampicin resistance in all four cases of multidrug-resistant TB but incorrectly identified resistance in three other patients whose disease was confirmed to be drug sensitive by gene sequencing (specificity, 94.1%; positive predictive value, 57%).
Conclusions
In this population of individuals at high risk of TB, intensive screening using the Xpert MTB/RIF assay increased case detection by 45% compared with smear microscopy, strongly supporting replacement of microscopy for this indication. However, despite the ability of the assay to rapidly detect rifampicin-resistant disease, the specificity for drug-resistant TB was sub-optimal.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Tuberculosis (TB)—a contagious bacterial infection that mainly affects the lungs—is a leading cause of illness and death among people who are infected with HIV, the virus that causes AIDS by destroying the immune system, which leaves infected individuals susceptible to other infections. TB is caused by Mycobacterium tuberculosis, which is spread in airborne droplets when people with the disease cough or sneeze. Its symptoms include a persistent cough, weight loss, and night sweats. Diagnostic tests for TB include chest X-rays, sputum smear analysis (microscopic examination of mucus coughed up from the lungs for M. tuberculosis bacilli), and mycobacterial liquid culture (the growth of M. tuberculosis from sputum and determination of its drug sensitivity). TB can be cured by taking several drugs daily for six months, although the recent emergence of multidrug-resistant TB (MDR-TB) is making the disease increasingly hard to treat.
Why Was This Study Done?
TB is a major problem in clinics that provide antiretroviral therapy (ART) for HIV-positive people in resource-limited settings. Not only is it a major cause of sickness and mortality in those affected by it, but TB (especially MDR-TB) can also spread to other patients attending the same clinic for health services. Rapid diagnosis and appropriate treatment are very important to reduce these risks. Unfortunately, sputum smear analysis—the mainstay of TB diagnosis in resource-limited settings—only detects about a fifth of TB cases when used as a screening tool before initiating ART. Chest X-rays are costly and don't always detect TB, and liquid culture—the gold standard method for TB diagnosis—is costly, technically difficult, and slow. Consequently, the World Health Organization (WHO) recently endorsed a new test for the investigation of patients suspected of having TB, especially in regions where HIV infection and MDR-TB are common. Xpert MTB/RIF is an automated DNA test that detects M. tuberculosis and DNA differences that make the bacteria resistant to the drug rifampicin (an indicator of MDR-TB) within 2 hours. In this study, the researchers investigate whether Xpert MTB/RIF could be used as a routine screening test to increase TB detection among HIV-positive people initiating ART.
What Did the Researchers Do and Find?
The researchers collected sputum from HIV-infected adults with no current TB diagnosis enrolling at an ART clinic in a South African township where HIV infection and TB are both common. They then compared the diagnostic accuracy of Xpert MTB/RIF (performed at a centralized laboratory) with that of several other tests, including liquid culture (the reference test). Nearly a fifth of the patients had culture-positive TB. Xpert MTB/RIF identified three-quarters of these patients (a sensitivity of 73.3%). By contrast, the sensitivity of smear microscopy was 28%. The new test's specificity (the proportion of patients with a negative Xpert MTB/RIF result among patients without TB) was 99.2%. That is, Xpert MTB/RIF had a low false-positive rate. Notably, Xpert MTB/RIF detected all cases of smear-positive, culture-positive TB but only 43.4% of smear-negative, culture-positive cases from a single sputum sample; it detected 62.3% of such cases when two sputum samples were analyzed. Finally, Xpert MTB/RIF correctly identified rifampicin resistance in all four patients who had MDR-TB but incorrectly identified resistance in three patients with drug-sensitive TB.
What Do These Findings Mean?
In this population of HIV-positive patients with a high TB risk, pre-ART screening with Xpert MTB/RIF increased case detection by 45% compared to smear microscopy, a finding that needs confirming in other settings. Importantly, Xpert MTB/RIF reduced the delay in diagnosis of TB from more than 20 days to two days. This delay would be reduced further by doing the assay at ART clinics rather than at a centralized testing facility, but the diagnostic accuracy of point-of-care testing needs evaluating. Overall, these findings (and those of an accompanying article by Scott et al. that examines the performance of Xpert MTB/RIF in an area where HIV infection is common) support the replacement of smear microscopy with Xpert MTB/RIF for pre-ART TB screening (provided misdiagnosis of rifampicin resistance can be reduced). These findings also suggest that routine screening with Xpert MTB/RIF could reduce the risk of MDR-TB outbreaks in HIV care and treatment settings and improve outcomes for HIV-positive patients with MDR-TB who currently often die before a diagnosis of TB can be made.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001056.
This study is further discussed in a PLoS Medicine Perspective by Carlton Evans; a related PLoS Medicine Research Article by Scott et al. is also available
WHO provides information (in several languages) on all aspects of tuberculosis, including general information on tuberculosis diagnostics and specific information on the Xpert MTB/RIF test; further information about WHO's endorsement of Xpert MTB/RIF is included in a recent Strategic and Technical Advisory Group for Tuberculosis report
WHO also provides information about tuberculosis and HIV
The US National Institute of Allergy and Infectious Diseases has detailed information on tuberculosis and HIV/AIDS
The US Centers for Disease Control and Prevention also has information about tuberculosis, including information on the diagnosis of and on tuberculosis and HIV co-infection
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV-related tuberculosis (in English and Spanish)
doi:10.1371/journal.pmed.1001067
PMCID: PMC3144215  PMID: 21818180
12.  Classification of Mycobacterium tuberculosis in Images of ZN-Stained Sputum Smears 
Screening for tuberculosis (TB) in low- and middle-income countries is centered on the microscope. We present methods for the automated identification of Mycobacterium tuberculosis in images of Ziehl–Neelsen (ZN) stained sputum smears obtained using a bright-field microscope. We segment candidate bacillus objects using a combination of two-class pixel classifiers. The algorithm produces results that agree well with manual segmentations, as judged by the Hausdorff distance and the modified Williams index. The extraction of geometric-transformation-invariant features and optimization of the feature set by feature subset selection and Fisher transformation follow. Finally, different two-class object classifiers are compared. The sensitivity and specificity of all tested classifiers is above 95% for the identification of bacillus objects represented by Fisher-transformed features. Our results may be used to reduce technician involvement in screening for TB, and would be particularly useful in laboratories in countries with a high burden of TB, where, typically, ZN rather than auramine staining of sputum smears is the method of choice.
doi:10.1109/TITB.2009.2028339
PMCID: PMC2953636  PMID: 19726269
Feature extraction; feature subset selection; microscopy; object classification; pixel classifiers; segmentation; tuberculosis (TB); Ziehl–Neelsen (ZN)
13.  Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study 
Lancet  2011;377(9776):1495-1505.
Summary
Background
The Xpert MTB/RIF test (Cepheid, Sunnyvale, CA, USA) can detect tuberculosis and its multidrug-resistant form with very high sensitivity and specificity in controlled studies, but no performance data exist from district and subdistrict health facilities in tuberculosis-endemic countries. We aimed to assess operational feasibility, accuracy, and effectiveness of implementation in such settings.
Methods
We assessed adults (≥18 years) with suspected tuberculosis or multidrug-resistant tuberculosis consecutively presenting with cough lasting at least 2 weeks to urban health centres in South Africa, Peru, and India, drug-resistance screening facilities in Azerbaijan and the Philippines, and an emergency room in Uganda. Patients were excluded from the main analyses if their second sputum sample was collected more than 1 week after the first sample, or if no valid reference standard or MTB/RIF test was available. We compared one-off direct MTB/RIF testing in nine microscopy laboratories adjacent to study sites with 2–3 sputum smears and 1–3 cultures, dependent on site, and drug-susceptibility testing. We assessed indicators of robustness including indeterminate rate and between-site performance, and compared time to detection, reporting, and treatment, and patient dropouts for the techniques used.
Findings
We enrolled 6648 participants between Aug 11, 2009, and June 26, 2010. One-off MTB/RIF testing detected 933 (90·3%) of 1033 culture-confirmed cases of tuberculosis, compared with 699 (67·1%) of 1041 for microscopy. MTB/RIF test sensitivity was 76·9% in smear-negative, culture-positive patients (296 of 385 samples), and 99·0% specific (2846 of 2876 non-tuberculosis samples). MTB/RIF test sensitivity for rifampicin resistance was 94·4% (236 of 250) and specificity was 98·3% (796 of 810). Unlike microscopy, MTB/RIF test sensitivity was not significantly lower in patients with HIV co-infection. Median time to detection of tuberculosis for the MTB/RIF test was 0 days (IQR 0–1), compared with 1 day (0–1) for microscopy, 30 days (23–43) for solid culture, and 16 days (13–21) for liquid culture. Median time to detection of resistance was 20 days (10–26) for line-probe assay and 106 days (30–124) for conventional drug-susceptibility testing. Use of the MTB/RIF test reduced median time to treatment for smear-negative tuberculosis from 56 days (39–81) to 5 days (2–8). The indeterminate rate of MTB/RIF testing was 2·4% (126 of 5321 samples) compared with 4·6% (441 of 9690) for cultures.
Interpretation
The MTB/RIF test can effectively be used in low-resource settings to simplify patients' access to early and accurate diagnosis, thereby potentially decreasing morbidity associated with diagnostic delay, dropout and mistreatment.
Funding
Foundation for Innovative New Diagnostics, Bill & Melinda Gates Foundation, European and Developing Countries Clinical Trials Partnership (TA2007.40200.009), Wellcome Trust (085251/B/08/Z), and UK Department for International Development.
doi:10.1016/S0140-6736(11)60438-8
PMCID: PMC3085933  PMID: 21507477
14.  Automated detection of tuberculosis in Ziehl-Neelsen stained sputum smears using two one-class classifiers 
Journal of microscopy  2010;237(1):96-102.
Screening for tuberculosis in high-prevalence countries relies on sputum smear microscopy. We present a method for the automated identification of Mycobacterium tuberculosis in images of Ziehl-Neelsen stained sputum smears obtained using a bright-field microscope. We use two stages of classification; the first implements a one-class pixel classifier, after which geometric transformation invariant features are extracted. The second stage employs one-class object classification. Different classifiers are compared; the sensitivity of all tested classifiers is above 90% for the identification of a single bacillus object using all extracted features. The mixture of Gaussians classifier performed well in both stages of classification. This method may be used as a step in the automation of tuberculosis screening, in order to reduce technician involvement in the process.
doi:10.1111/j.1365-2818.2009.03308.x
PMCID: PMC2825536  PMID: 20055923
15.  Ventricular lavage for post-haemorrhagic hydrocephalus 
Cerebrospinal Fluid Research  2010;7(Suppl 1):S49.
doi:10.1186/1743-8454-7-S1-S49
PMCID: PMC3026528
16.  Randomised trial of a parenting intervention during neonatal intensive care 
Objective
To evaluate the influence of parenting intervention on maternal responsiveness and infant neurobehavioural development following a very premature birth.
Design
Cluster‐randomised controlled trial, with a crossover design and three‐month washout period.
Setting
Six neonatal intensive care units.
Patients
Infants born <32 weeks' gestation.
Intervention
The Parent Baby Interaction Programme (PBIP) is a supportive, educational intervention delivered by research nurses in the neonatal intensive care unit, with optional home follow‐up for up to six weeks after discharge.
Main outcome measures
Parenting stress at 3 months adjusted age, as measured by the Parenting Stress Index (PSI). Other outcomes included the Neurobehavioural Assessment of the Preterm Infant (NAPI) and maternal interaction as assessed by the Nursing Child Assessment Teaching Scale (NCATS) and the responsivity subscale for Home Observation for Measurement of the Environment (HOME).
Results
112 infants were recruited in the intervention phases and 121 in the control phases. Mean standardised NAPI scores at 35 weeks did not differ between the PBIP and control groups. Both groups had low but similar NCATS caregiver scores before discharge (36.6 in the PBIP group and 37.4 in control, adjusted mean difference −0.7, 95% CI −2.7 to 1.4). At three months, adjusted age mean PSI scores for the PBIP group were 71.9 compared with 67.1 for controls (adjusted mean difference 3.8, 95% CI −4.7 to 12.4). NCATS scores and HOME responsivity scores were similarly distributed between the groups.
Conclusion
This early, nurse‐delivered, parent‐focused interaction programme intervention had no measurable effects on short‐term infant neurobehavioural function, mother–child interaction or parenting stresses.
doi:10.1136/adc.2006.103135
PMCID: PMC2675386  PMID: 17301114
cluster randomised trial; interaction; parental stress; preterm infant; very premature birth
17.  Molecular epidemiology of Mycobacterium tuberculosis in a South African community with high HIV prevalence 
The Journal of infectious diseases  2009;200(8):1207-1211.
To explore the relationship between human immunodeficiency virus (HIV) and M. tuberculosis genotypes we performed IS6110-based restriction fragment length polymorphism analysis on M. tuberculosis culture specimens from smear-positive TB cases in a peri-urban community in South Africa from 2001-2005. Among 151 isolates, 95 strains were identified within 26 families with 54% clustering. HIV status was associated with W-Beijing strains (p=0.009) but not with clustering per se. High frequency of clustering suggests ongoing transmission in both HIV-negative and HIV-positive individuals in this community. The strong association of W-Beijing with HIV-infection may have important implications for tuberculosis control.
doi:10.1086/605930
PMCID: PMC2932637  PMID: 19764885
Molecular epidemiology; RFLP; Tuberculosis; HIV; Geographical Information System; W-Beijing
18.  The association between birth condition and neuropsychological functioning and educational attainment at school age: a cohort study 
Objective
Poor condition at birth may impact on IQ, although its effect on other measures of neurodevelopment is unclear. The authors' aim was to determine whether infants receiving resuscitation after birth have reduced scores in measures of attention, memory and language skills or the need for educational support at school even in the absence of clinical encephalopathy.
Methods
Three groups of term infants were identified from the Avon longitudinal study of parents and children: infants resuscitated at birth but asymptomatic for encephalopathy (n=612), infants resuscitated who developed symptoms of encephalopathy (n=40) and the reference infants who were not resuscitated and had no further neonatal care (n=8080). Measures of attention, language, memory and the need for educational support were obtained for children between 8 years and 11 years. Test results (standardised to a mean of 100 and SD of 15) were adjusted for clinical and social covariates. Missing covariate data were imputed using chained equations.
Results
Infants asymptomatic after resuscitation had similar scores to those not requiring resuscitation for all measures while infants who developed encephalopathy had lower working memory (−6.65 (−12.34 to −0.96)), reading accuracy (−7.95 (−13.28 to −2.63)) and comprehension (−9.32 (−14.47 to −4.17) scores and increased risk of receiving educational support (OR 6.24 (1.52 to 26.43)) than infants thought to be well at birth, although there was little evidence for an association after excluding infants who developed cerebral palsy.
Conclusions
The authors found no evidence that infants who were resuscitated but remained well afterwards differed from those not requiring resuscitation in the aspects of neuropsychological functioning assessed in this study. Infants who developed neonatal encephalopathy had evidence of worse functioning, particularly in language skills and were more likely to receive educational support at school.
doi:10.1136/adc.2009.176065
PMCID: PMC3015086  PMID: 20705720
19.  Clinical Utility of a Commercial LAM-ELISA Assay for TB Diagnosis in HIV-Infected Patients Using Urine and Sputum Samples 
PLoS ONE  2010;5(3):e9848.
Background
The accurate diagnosis of TB in HIV-infected patients, particularly with advanced immunosuppression, is difficult. Recent studies indicate that a lipoarabinomannan (LAM) assay (Clearview-TB®-ELISA) may have some utility for the diagnosis of TB in HIV-infected patients; however, the precise subgroup that may benefit from this technology requires clarification. The utility of LAM in sputum samples has, hitherto, not been evaluated.
Methods
LAM was measured in sputum and urine samples obtained from 500 consecutively recruited ambulant patients, with suspected TB, from 2 primary care clinics in South Africa. Culture positivity for M. tuberculosis was used as the reference standard for TB diagnosis.
Results
Of 440 evaluable patients 120/387 (31%) were HIV-infected. Urine-LAM positivity was associated with HIV positivity (p = 0.007) and test sensitivity, although low, was significantly higher in HIV-infected compared to uninfected patients (21% versus 6%; p<0.001), and also in HIV-infected participants with a CD4 <200 versus >200 cells/mm3 (37% versus 0%; p = 0.003). Urine-LAM remained highly specific in all 3 subgroups (95%–100%). 25% of smear-negative but culture-positive HIV-infected patients with a CD4 <200 cells/mm3 were positive for urine-LAM. Sputum-LAM had good sensitivity (86%) but poor specificity (15%) likely due to test cross-reactivity with several mouth-residing organisms including actinomycetes and nocardia species.
Conclusions
These preliminary data indicate that in a high burden primary care setting the diagnostic usefulness of urine-LAM is limited, as a rule-in test, to a specific patient subgroup i.e. smear-negative HIV-infected TB patients with a CD4 count <200 cells/mm3, who would otherwise have required further investigation. However, even in this group sensitivity was modest. Future and adequately powered studies in a primary care setting should now specifically target patients with suspected TB who have advanced HIV infection.
doi:10.1371/journal.pone.0009848
PMCID: PMC2844421  PMID: 20352098
20.  Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data 
Objective To determine whether moderate hypothermia after hypoxic-ischaemic encephalopathy in neonates improves survival and neurological outcome at 18 months of age.
Design A meta-analysis was performed using a fixed effect model. Risk ratios, risk difference, and number needed to treat, plus 95% confidence intervals, were measured.
Data sources Studies were identified from the Cochrane central register of controlled trials, the Oxford database of perinatal trials, PubMed, previous reviews, and abstracts.
Review methods Reports that compared whole body cooling or selective head cooling with normal care in neonates with hypoxic-ischaemic encephalopathy and that included data on death or disability and on specific neurological outcomes of interest to patients and clinicians were selected.
Results We found three trials, encompassing 767 infants, that included information on death and major neurodevelopmental disability after at least 18 months’ follow-up. We also identified seven other trials with mortality information but no appropriate neurodevelopmental data. Therapeutic hypothermia significantly reduced the combined rate of death and severe disability in the three trials with 18 month outcomes (risk ratio 0.81, 95% confidence interval 0.71 to 0.93, P=0.002; risk difference −0.11, 95% CI −0.18 to −0.04), with a number needed to treat of nine (95% CI 5 to 25). Hypothermia increased survival with normal neurological function (risk ratio 1.53, 95% CI 1.22 to 1.93, P<0.001; risk difference 0.12, 95% CI 0.06 to 0.18), with a number needed to treat of eight (95% CI 5 to 17), and in survivors reduced the rates of severe disability (P=0.006), cerebral palsy (P=0.004), and mental and the psychomotor developmental index of less than 70 (P=0.01 and P=0.02, respectively). No significant interaction between severity of encephalopathy and treatment effect was detected. Mortality was significantly reduced when we assessed all 10 trials (1320 infants; relative risk 0.78, 95% CI 0.66 to 0.93, P=0.005; risk difference −0.07, 95% CI −0.12 to −0.02), with a number needed to treat of 14 (95% CI 8 to 47).
Conclusions In infants with hypoxic-ischaemic encephalopathy, moderate hypothermia is associated with a consistent reduction in death and neurological impairment at 18 months.
doi:10.1136/bmj.c363
PMCID: PMC2819259  PMID: 20144981
21.  Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic–ischaemic encephalopathy: a nested substudy of a randomised controlled trial 
Lancet Neurology  2010;9(1):39-45.
Summary
Background
Moderate hypothermia in neonates with hypoxic–ischaemic encephalopathy might improve survival and neurological outcomes at up to 18 months of age, although complete neurological assessment at this age is difficult. To ascertain more precisely the effect of therapeutic hypothermia on neonatal cerebral injury, we assessed cerebral lesions on MRI scans of infants who participated in the Total Body Hypothermia for Neonatal Encephalopathy (TOBY) trial.
Methods
In the TOBY trial hypoxic–ischaemic encephalopathy was graded clinically according to the changes seen on amplitude integrated EEG, and infants were randomly assigned to intensive care with or without cooling by central telephone randomisation. The relation between allocation to hypothermia or normothermia and cerebral lesions was assessed by logistic regression with perinatal factors as covariates, and adjusted odds ratios (ORs) were calculated. The TOBY trial is registered, number ISRCTN 89547571.
Findings
325 infants were recruited in the TOBY trial between 2002 and 2006. Images were available for analysis from 131 infants. Therapeutic hypothermia was associated with a reduction in lesions in the basal ganglia or thalamus (OR 0·36, 95% CI 0·15–0·84; p=0·02), white matter (0·30, 0·12–0·77; p=0·01), and abnormal posterior limb of the internal capsule (0·38, 0·17–0·85; p=0·02). Compared with non-cooled infants, cooled infants had fewer scans that were predictive of later neuromotor abnormalities (0·41, 0·18–0·91; p=0·03) and were more likely to have normal scans (2·81, 1·13–6·93; p=0·03). The accuracy of prediction by MRI of death or disability to 18 months of age was 0·84 (0·74–0·94) in the cooled group and 0·81 (0·71–0·91) in the non-cooled group.
Interpretation
Therapeutic hypothermia decreases brain tissue injury in infants with hypoxic–ischaemic encephalopathy. The predictive value of MRI for subsequent neurological impairment is not affected by therapeutic hypothermia.
Funding
UK Medical Research Council; UK Department of Health.
doi:10.1016/S1474-4422(09)70295-9
PMCID: PMC2795146  PMID: 19896902
22.  Resuscitation at birth and cognition at 8 years of age: a cohort study 
Lancet  2009;373(9675):1615-1622.
Summary
Background
Mild cerebral injury might cause subtle defects in cognitive function that are only detectable as the child grows older. Our aim was to determine whether infants receiving resuscitation after birth, but with no symptoms of encephalopathy, have reduced intelligence quotient (IQ) scores in childhood.
Methods
Three groups of infants were selected from the Avon Longitudinal Study of Parents and Children: infants who were resuscitated at birth but were asymptomatic for encephalopathy and had no further neonatal care (n=815), those who were resuscitated and had neonatal care for symptoms of encephalopathy (n=58), and the reference group who were not resuscitated, were asymptomatic for encephalopathy, and had no further neonatal care (n=10 609). Cognitive function was assessed at a mean age of 8·6 years (SD 0·33); a low IQ score was defined as less than 80. IQ scores were obtained for 5953 children with a shortened version of the Weschler intelligence scale for children (WISC-III), the remaining 5529 were non-responders. All children did not complete all parts of the test, and therefore multiplied IQ values comparable to the full-scale test were only available for 5887 children. Results were adjusted for clinical and social covariates. Chained equations were used to impute missing values of covariates.
Findings
In the main analysis at 8 years of age (n=5887), increased risk of a low IQ score was recorded in both resuscitated infants asymptomatic for encephalopathy (odds ratio 1·65 [95% CI 1·13–2·43]) and those with symptoms of encephalopathy (6·22 [1·57–24·65]). However, the population of asymptomatic infants was larger than that of infants with encephalopathy, and therefore the population attributable risk fraction for an IQ score that might be attributable to the need for resuscitation at birth was 3·4% (95% CI 0·5–6·3) for asymptomatic infants and 1·2% (0·2–2·2) for those who developed encephalopathy.
Interpretation
Infants who were resuscitated had increased risk of a low IQ score, even if they remained healthy during the neonatal period. Resuscitated infants asymptomatic for encephalopathy might result in a larger proportion of adults with low IQs than do those who develop neurological symptoms consistent with encephalopathy.
Funding
Wellcome Trust.
doi:10.1016/S0140-6736(09)60244-0
PMCID: PMC2688587  PMID: 19386357
23.  Clinical Diagnostic Utility of IP-10 and LAM Antigen Levels for the Diagnosis of Tuberculous Pleural Effusions in a High Burden Setting 
PLoS ONE  2009;4(3):e4689.
Background
Current tools for the diagnosis of tuberculosis pleural effusions are sub-optimal. Data about the value of new diagnostic technologies are limited, particularly, in high burden settings. Preliminary case control studies have identified IFN-γ-inducible-10kDa protein (IP-10) as a promising diagnostic marker; however, its diagnostic utility in a day-to-day clinical setting is unclear. Detection of LAM antigen has not previously been evaluated in pleural fluid.
Methods
We investigated the comparative diagnostic utility of established (adenosine deaminase [ADA]), more recent (standardized nucleic-acid-amplification-test [NAAT]) and newer technologies (a standardized LAM mycobacterial antigen-detection assay and IP-10 levels) for the evaluation of pleural effusions in 78 consecutively recruited South African tuberculosis suspects. All consenting participants underwent pleural biopsy unless contra-indicated or refused. The reference standard comprised culture positivity for M. tuberculosis or histology suggestive of tuberculosis.
Principal Findings
Of 74 evaluable subjects 48, 7 and 19 had definite, probable and non-TB, respectively. IP-10 levels were significantly higher in TB vs non-TB participants (p<0.0001). The respective outcomes [sensitivity, specificity, PPV, NPV %] for the different diagnostic modalities were: ADA at the 30 IU/L cut-point [96; 69; 90; 85], NAAT [6; 93; 67; 28], IP-10 at the 28,170 pg/ml ROC-derived cut-point [80; 82; 91; 64], and IP-10 at the 4035 pg/ml cut-point [100; 53; 83; 100]. Thus IP-10, using the ROC-derived cut-point, missed ∼20% of TB cases and mis-diagnosed ∼20% of non-TB cases. By contrast, when a lower cut-point was used a negative test excluded TB. The NAAT had a poor sensitivity but high specificity. LAM antigen-detection was not diagnostically useful.
Conclusion
Although IP-10, like ADA, has sub-optimal specificity, it may be a clinically useful rule-out test for tuberculous pleural effusions. Larger multi-centric studies are now required to confirm our findings.
doi:10.1371/journal.pone.0004689
PMCID: PMC2650091  PMID: 19277111
24.  Bacterial Disease and Antimicrobial Susceptibility Patterns in HIV-Infected, Hospitalized Children: A Retrospective Cohort Study 
PLoS ONE  2008;3(9):e3260.
Background
Serious bacterial infections are a major source of morbidity and mortality in HIV-infected children. The spectrum of disease is wide, and responsible organisms vary according to setting. The use of antibiotic prophylaxis and the emergence of multi-drug resistant bacteria necessitate examination of responsible organisms and their antibiotic susceptibility.
Methodology/Principal Findings
A retrospective cohort study of all HIV-positive pediatric admissions at an urban public sector hospital in Cape Town between January 2002 and June 2006 was conducted. Children between the ages of one month and nine years with laboratory confirmed HIV status, serious bacterial infection, and a hospital length of stay of 5 days or more, were eligible for inclusion. Organisms isolated from blood, urine, and cerebral spinal fluid cultures and their antimicrobial susceptibility were examined, and compared according to timing of isolation to distinguish nosocomial versus community-acquired. One hundred and forty-one children were identified (median age 1.2 years), 39% of whom were on antiretrovirals started before or during this hospitalization. Bacterial infections involved all organ systems, however pneumonia was most common (67%). S. pneumoniae and S. aureus were the most common gram positive and K. pneumoniae was the most common gram negative organism. K pneumoniae isolates were resistant to many first and second line antibiotics, and were all considered nosocomial. All S. aureus isolates were methicillin resistant, some of which were community-acquired.
Conclusions/Significance
Bacterial infections are an important source of co-morbidity in HIV-infected children in resource-limited settings. Clinicians should have a low threshold to initiate antibiotics in children requiring hospitalization. Broad-spectrum antibiotics should be used judiciously. Clinicians caring for HIV-infected children should be cognizant of the most common organisms affecting such children, and of their local antimicrobial susceptibilities, when treating empirically for serious bacterial infections.
doi:10.1371/journal.pone.0003260
PMCID: PMC2533121  PMID: 18813340
25.  The TOBY Study. Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: A randomised controlled trial 
BMC Pediatrics  2008;8:17.
Background
A hypoxic-ischaemic insult occurring around the time of birth may result in an encephalopathic state characterised by the need for resuscitation at birth, neurological depression, seizures and electroencephalographic abnormalities. There is an increasing risk of death or neurodevelopmental abnormalities with more severe encephalopathy. Current management consists of maintaining physiological parameters within the normal range and treating seizures with anticonvulsants.
Studies in adult and newborn animals have shown that a reduction of body temperature of 3–4°C after cerebral insults is associated with improved histological and behavioural outcome. Pilot studies in infants with encephalopathy of head cooling combined with mild whole body hypothermia and of moderate whole body cooling to 33.5°C have been reported. No complications were noted but the group sizes were too small to evaluate benefit.
Methods/Design
TOBY is a multi-centre, prospective, randomised study of term infants after perinatal asphyxia comparing those allocated to "intensive care plus total body cooling for 72 hours" with those allocated to "intensive care without cooling".
Full-term infants will be randomised within 6 hours of birth to either a control group with the rectal temperature kept at 37 +/- 0.2°C or to whole body cooling, with rectal temperature kept at 33–34°C for 72 hours. Term infants showing signs of moderate or severe encephalopathy +/- seizures have their eligibility confirmed by cerebral function monitoring. Outcomes will be assessed at 18 months of age using neurological and neurodevelopmental testing methods.
Sample size
At least 236 infants would be needed to demonstrate a 30% reduction in the relative risk of mortality or serious disability at 18 months.
Recruitment was ahead of target by seven months and approvals were obtained allowing recruitment to continue to the end of the planned recruitment phase. 325 infants were recruited.
Primary outcome
Combined rate of mortality and severe neurodevelopmental impairment in survivors at 18 months of age. Neurodevelopmental impairment will be defined as any of:
• Bayley mental developmental scale score less than 70
• Gross Motor Function Classification System Levels III – V
• Bilateral cortical visual impairments
Trial Registration
Current Controlled Trials ISRCTN89547571
doi:10.1186/1471-2431-8-17
PMCID: PMC2409316  PMID: 18447921

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