Browsing by Author "Walters, Elisabetta"
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- ItemClinical presentation and outcome of tuberculosis in human immunodeficiency virus infected children on anti-retroviral therapy(BioMed Central, 2008-01) Walters, Elisabetta; Cotton, Mark F.; Rabie, Helena; Schaaf, H. Simon; Walters, Lourens O.; Marais, Ben J.Background: The tuberculosis (TB) and human immunodeficiency virus (HIV) epidemics are poorly controlled in sub-Saharan Africa, where highly active antiretroviral treatment (HAART) has become more freely available. Little is known about the clinical presentation and outcome of TB in HIV-infected children on HAART. Methods: We performed a comprehensive file review of all children who commenced HAART at Tygerberg Children's Hospital from January 2003 through December 2005. Results: Data from 290 children were analyzed; 137 TB episodes were recorded in 136 children; 116 episodes occurred before and 21 after HAART initiation; 10 episodes were probably related to immune reconstitution inflammatory syndrome (IRIS). The number of TB cases per 100 patient years were 53.3 during the 9 months prior to HAART initiation, and 6.4 during post HAART follow-up [odds ratio (OR) 16.6; 95% confidence interval (CI) 12.5–22.4]. A positive outcome was achieved in 97/137 (71%) episodes, 6 (4%) cases experienced no improvement, 16 (12%) died and the outcome could not be established in 18 (13%). Mortality was less in children on HAART (1/21; 4.8%) compared to those not on HAART (15/116; 12.9%). Conclusion: We recorded an extremely high incidence of TB among HIV-infected children, especially prior to HAART initiation. Starting HAART at an earlier stage is likely to reduce morbidity and mortality related to TB, particularly in TB-endemic areas. Management frequently deviated from standard guidelines, but outcomes in general were good.
- ItemComplementary surveillance strategies are needed to better characterise the epidemiology, care pathways and treatment outcomes of tuberculosis in children(BioMed Central, 2018-03-23) Du Preez, Karen; Schaaf, H. Simon; Dunbar, Rory; Walters, Elisabetta; Swartz, Alvera; Solomons, Regan; Hesseling, Anneke C.Background: Tuberculosis (TB) in young and HIV-infected children is frequently diagnosed at hospital level. In settings where general hospitals do not function as TB reporting units, the burden and severity of childhood TB may not be accurately reflected in routine TB surveillance data. Given the paucibacillary nature of childhood TB, microbiological surveillance alone will miss the majority of hospital-managed children. The study objective was to combine complementary hospital-based surveillance strategies to accurately report the burden, spectrum and outcomes of childhood TB managed at referral hospital-level in a high TB burden setting. Methods: We conducted a prospective cohort study including all children (< 13 years) managed for TB at a large referral hospital in Cape Town, South Africa during 2012. Children were identified through newly implemented clinical surveillance in addition to existing laboratory surveillance. Data were collected from clinical patient records, the National Health Laboratory Service database, and provincial electronic TB registers. Descriptive statistics were used to report overall TB disease burden, spectrum, care pathways and treatment outcomes. Univariate analysis compared characteristics between children identified through the two hospital-based surveillance strategies to characterise the group of children missed by existing laboratory surveillance. Results: During 2012, 395 children (180 [45.6%] < 2 years) were managed for TB. Clinical surveillance identified 237 (60%) children in addition to laboratory surveillance. Ninety (24.3%) children were HIV co-infected; 113 (29.5%) had weight-for-age z-scores <− 3. Extra-pulmonary TB (EPTB) was diagnosed in 188 (47.6%); 77 (19.5%) with disseminated TB. Favourable TB treatment outcomes were reported in 300/344 (87.2%) children with drugsusceptible and 50/51 (98.0%) children with drug-resistant TB. Older children (OR 1.7; 95% CI 1.0–2.8), children with EPTB (OR 2.3; 95% CI 1.5–3.6) and in-hospital deaths (OR 5.4; 95% CI 1.1–26.9) were more frequently detected by laboratory surveillance. TB/HIV co-infected children were less likely to be identified through laboratory surveillance (OR 0.3; 95% CI 0.2–0.5). Conclusions: The burden and spectrum of childhood TB disease managed at referral hospital level in high burden settings is substantial. Hospital-based surveillance in addition to routine TB surveillance is essential to provide a complete picture of the burden, spectrum and impact of childhood TB in settings where hospitals are not TB reporting units.
- ItemInnovative strategies to improve the diagnosis of intrathoracic tuberculosis in children(Stellenbosch : Stellenbosch University, 2018-12) Walters, Elisabetta; Hesseling, Anneke Catharina; Gie, Robert Peter; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.ENGLISH ABSTRACT: Paediatric tuberculosis (TB) contributes approximately 10% of the global TB burden, with over one million estimated new cases and 253,000 TB-related deaths in children during 2016. Paediatric TB is a particular problem in low and middle income countries. However, the majority of paediatric cases were not notified to National TB Programs or the World Health Organization and >96% of deaths were estimated to have occurred in children who were not receiving antituberculosis treatment. Young, HIVinfected and malnourished children progress rapidly from infection with Mycobacterium tuberculosis (M.tb) to TB, and are at exquisite risk of significant morbidity and mortality from complicated and disseminated forms of TB. The challenges around the diagnosis and microbiological confirmation of pulmonary TB (PTB), the most common manifestation of TB disease in children, contribute to poor access to appropriate treatment and to underreporting. The diagnosis of TB in young children typically relies on the evaluation of clinical symptoms and epidemiological factors, and, if available, includes tests of TB infection and chest radiology. All of these tools have considerable limitations and cannot reliably confirm or exclude a diagnosis of PTB. However, the bacteriological confirmation of PTB in children requires the collection of respiratory specimens using procedures that are both relatively invasive and resource-intensive. Furthermore, the current gold standard of diagnosis, mycobacterial culture, has low sensitivity (approximately 30%) and long turnaround time (up to 6 weeks) in children, who typically have paucibacillary TB (low bacillary load). In resource-limited settings, the capacity for respiratory sampling of young children is typically low. These diagnostic challenges prevent adequate reporting and global surveillance of paediatric TB. Diagnostic uncertainty also compromises the clinical management of paediatric PTB, resulting in over- and under-treatment, and has resulted in the systematic exclusion of children from much-needed interventional research, including tuberculosis treatment trials. Diagnostic research in paediatric PTB has also been poorly standardised, making generalizability and comparability of results difficult. In addition, the insensitive reference standard has hindered progress towards the development of new diagnostic tests tailored for children. In an effort to develop and investigate more feasible strategies to improve and promote microbiological testing of children with suspected PTB living in high TB-burden settings, I enrolled a large well-characterized cohort of children presenting to hospital with suspected PTB. Children were thoroughly investigated, using standard approaches and intensive specimen collection for liquid culture and molecular testing by Xpert ® MTB/RIF (Xpert). Chest radiographs were dual read by blinded experts and reported using standard forms. All children were followed regardless of their final diagnosis and the spectrum of TB and non-TB disease was well described. I evaluated a number of novel diagnostic strategies, including the use of stool specimens for diagnosis of PTB using culture and Xpert, using different stool processing methods, and pooling respiratory specimens to improve the diagnostic yield and reduce the cost of laboratory testing. Importantly, I developed a framework for future evaluation of novel diagnostic tools/ biomarkers for the diagnosis of PTB in children. The total cohort included 608 children and was representative of the demographics and spectrum of disease observed in many high TB-burden settings, where young children bear the highest burden of TB disease. The median age of the cohort was 16.2 months, with 11.8% HIV-infected. Infants below 6 months of age constituted almost 15% of the total cohort. More than 20% of children had a non-specific clinical presentation, with similar prevalence of acute respiratory symptoms across all age groups and diagnostic categories. Radiological features not typically associated with PTB were common, and indicate a high burden of respiratory pathology as well as potentially non-typical radiological manifestations of PTB. Two hundred and eighty-one (46.2%) children were diagnosed with PTB and were prescribed antituberculosis treatment: 117 (41.6%) were microbiologically confirmed by Xpert or culture, which represents a high diagnostic yield, considering that approximately 50% of children with PTB had nonsevere pulmonary disease. In addition, 20/327 (6.6%) children initially considered symptomatic controls were initiated on antituberculosis treatment within two months of enrolment, due to poor clinical progress or positive results from baseline and follow-up bacteriological investigations. This emphasizes the importance and utility of careful specimen collection, incorporating different specimen types and different diagnostic tests and of follow-up of all children in whom there is a clinical suspicion of PTB. An unexpectedly high proportion of young infants <6 months of age had severe PTB, including cavities, associated with high bacillary load and smear-positivity. In addition, young infants and HIV-infected children were high-risk groups for disseminated TB. This calls for urgent priority to be given towards the development of tailored diagnostic tests that can rapidly confirm and quantify M.tb disease in the youngest children, and in the early stages of disease, prior to rapid progression to severe TB. Careful consideration should be given to infection control measures when managing and investigating children, including young infants with suspected PTB. I showed that stool as a specimen was useful to confirm M.tb using Xpert in children with severe pulmonary disease, particularly in children with cavities on chest radiograph, detecting 45% of those who were bacteriologically confirmed on respiratory specimens. A novel centrifugation-free processing method for stool specimens (stool processing kit) showed similar results to the more laborious, centrifugation-dependent methods I initially investigated. This new approach could be used with more sensitive molecular assays in future to improve stool-based diagnosis of PTB in children. In contrast, stool culture had limited value in the detection of M.tb, primarily due to very high contamination (>41% of stool cultures) using standard N-acetyl-l-cysteine–sodium hydroxide (NALC-NaOH 1.25%) decontamination protocols. Finally, I showed that pooling up to three respiratory specimens of different types (gastric aspirate, induced sputum and nasopharyngeal aspirate) per child, in children who could not expectorate sputum, had similar diagnostic yield by Xpert and culture as individually testing the same three single respiratory specimens. In paired analyses, pooled specimens had significantly higher overall yield than induced sputum and nasopharyngeal aspirate alone, but had similar diagnostic yield as a single gastric aspirate (86.5% vs. 74.4% respectively, p=0.46). The overall yield of three individual specimens tested individually was 86% of all confirmed cases, similar to the overall yield of pooled specimens. These results support the substantial diagnostic value of a single gastric aspirate using culture and Xpert, and of “front-loading” specimens of different types on one day to improve the feasibility of specimen collection in young children. Through this cohort study, I collected comprehensive follow-up data documenting response to antituberculosis treatment and clinical progress in children not receiving antituberculosis treatment (symptomatic controls), to 6 months. These data will be further analysed to validate recently proposed clinical case definitions for TB diagnostic research in children, including the diagnostic value of clinical and other follow-up measures. Symptomatic controls who initially presented with symptoms suggestive of PTB will be further analysed to better understand the spectrum of non-TB respiratory disease borne by children from high-TB burden settings. I have also established a bio-repository of well-characterised blood and urine specimens for evaluation of promising diagnostic and prognostic biomarkers of TB disease in children. In summary, through this body of research, I have generated novel data on the utility of several feasible diagnostic strategies for the diagnosis of PTB in HIV-infected and uninfected children from high TB-burden settings. I have analysed these data in relation to relevant clinical and laboratory characteristics in order to make specific recommendations on the most appropriate placement of these strategies, considering both target populations and different levels of health care. I was able to do this by carrying out a well-designed study, in a well-described cohort and by comprehensively reporting on all aspects of the study, including non-evaluable results and complex clinical scenarios. These aspects should be considered when future diagnostic studies for paediatric PTB are being designed, implemented and reported. I have created a rigorous framework for the evaluation of future novel diagnostic strategies, and I have identified numerous areas which require further research and intervention.
- ItemStool culture for diagnosis of pulmonary tuberculosis in children(American Society for Microbiology, 2017-12) Walters, Elisabetta; Demers, Anne-Marie; Van der Zalm, Marieke M.; Whitelaw, Andrew; Palmer, Megan; Bosch, Corne; Draper, Heather R.; Gie, Robert P.; Hesseling, Anneke C.Bacteriological confirmation of Mycobacterium tuberculosis is achieved in the minority of young children with tuberculosis (TB), since specimen collection is resource intensive and respiratory secretions are mostly paucibacillary, leading to limited sensitivity of available diagnostic tests. Although molecular tests are increasingly available globally, mycobacterial culture remains the gold standard for diagnosis and determination of drug susceptibility and is more sensitive than molecular methods for paucibacillary TB. We evaluated stool culture as an alternative to respiratory specimens for the diagnosis of suspected intrathoracic TB in a subgroup of 188 children (median age, 14.4 months; 15.4% HIV infected) enrolled in a TB diagnostic study at two local hospitals in Cape Town, South Africa. One stool culture was compared to overall bacteriological confirmation by stool Xpert and by Xpert and culture of multiple respiratory specimens. After decontamination/digestion with NALC (N-acetyl-l-cysteine)-NaOH (1.25%), concentrated fluorescent smear microscopy, Xpert MTB/RIF, and liquid culture were completed for all specimens. Culture contamination of stool specimens was high at 41.5%. Seven of 90 (7.8%) children initiating TB treatment were stool culture positive for M. tuberculosis. Excluding contaminated cultures, the sensitivity of stool culture versus confirmed TB was 6/25 (24.0%; 95% confidence interval [CI] = 9.4 to 45.1%). In addition, stool culture detected TB in 1/93 (1.1%) children with “unconfirmed TB.” Testing the same stool by Xpert increased sensitivity to 33.3% (95% CI = 18.0 to 51.8%). In conclusion, stool culture had low sensitivity for M. tuberculosis detection in children with intrathoracic TB. Reducing culture contamination through improved laboratory protocols may enable more reliable estimates of its diagnostic utility.
- ItemUtility of host markers detected in Quantiferon supernatants for the diagnosis of tuberculosis in children in a high-burden setting(PLoS, 2013-05-15) Chegou, Novel N.; Detjen, Anne K.; Thiart, Lani; Walters, Elisabetta; Mandalakas, Anna M.; Hesseling, Anneke C.; Walzl, GerhardBackground: The diagnosis of childhood tuberculosis (TB) disease remains a challenge especially in young and HIV-infected children. Recent studies have identified potential host markers which, when measured in Quantiferon (QFT-IT) supernatants, show promise in discriminating between Mycobacterium tuberculosis (M.tb) infection states. In this study, the utility of such markers was investigated in children screened for TB in a setting with high TB incidence. Methodology and Principal Findings: 76 children (29% HIV-infected) with or without active TB provided blood specimens collected directly into QFT-IT tubes. After overnight incubation, culture supernatants were harvested, aliquoted and frozen for future immunological research purposes. Subsequently, the levels of 12 host markers previously identified as potential TB diagnostic markers were evaluated in these supernatants for their ability to discriminate between M.tb infection and disease states using the Luminex platform. Of the 76 children included, 19 (25%) had culture confirmed TB disease; 26 (46%) of the 57 without TB had positive markers of M.tb infection defined by a positive QFT-IT test. The potentially most useful analytes for diagnosing TB disease included IFN-a2, IL-1Ra, sCD40L and VEGF and the most useful markers for discriminating between QFT-IT positive children as TB or latent infection included IL-1Ra, IP-10 and VEGF. When markers were used in combinations of four, 84% of all children were accurately classified into their respective groups (TB disease or no TB), after leave-one-out cross validation. Conclusions: Measurement of the levels of IFN-a2, IL-1Ra, sCD40L, IP-10 and VEGF in QFT-IT supernatants may be a useful method for diagnosing TB disease and differentiating between active TB disease and M.tb infection in children. Our observations warrant further investigation in larger well-characterized clinical cohorts.