Publications by authors named "Elisabetta Walters"

22 Publications

  • Page 1 of 1

Diagnostic utility of bronchoalveolar lavage in children with complicated intrathoracic tuberculosis.

Pediatr Pulmonol 2021 Jul 13;56(7):2186-2194. Epub 2021 Apr 13.

Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Introduction: Bronchoscopy can be a useful tool in children with pulmonary tuberculosis (PTB) with severe disease potentially requiring intervention or in the face of diagnostic dilemmas. The aim of this study was to determine the value of Xpert MTB/RIF assay (Xpert) on bronchoalveolar lavage (BAL) samples in children with complicated PTB.

Methods: Retrospective analysis of children with clinically diagnosed PTB, who underwent routine bronchoscopy over a 5-year period at a large referral hospital. BAL and other respiratory samples were tested by microscopy, culture, and Xpert. We explored whether clinical, radiographic and bronchoscopy findings, and duration of antituberculosis treatment were associated with bacteriological confirmation.

Results: One hundred and twelve out of one hundred and forty-six (76.7%) children (median age 16 months) were on antituberculosis treatment for a median of 10 days at the time of bronchoscopy. Overall, bacteriological confirmation was achieved in 115 (78.7%), with 101 (69.2%) detected on BAL. Of those bacteriologically confirmed on BAL, 61.4% were positive by both Xpert and culture, 34.7% only by Xpert, and 3.9% only by culture. Sensitivity and specificity of Xpert compared with culture on BAL samples for children not on antituberculosis treatment were 94.1% (95% confidence interval [CI]: 71.3, 99.8) and 68.7% (95% CI: 41.3, 89.0), respectively.

Conclusions: In children undergoing bronchoscopy for complicated PTB, Xpert testing of BAL had a high diagnostic yield in children already on antituberculosis treatment. Bronchoscopy should be considered if noninvasive respiratory specimens fail to confirm complicated TB.
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http://dx.doi.org/10.1002/ppul.25405DOI Listing
July 2021

Development of a treatment-decision algorithm for HIV-uninfected children evaluated for pulmonary tuberculosis.

Clin Infect Dis 2021 Jan 15. Epub 2021 Jan 15.

Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University and Department of Infectious Diseases, Imperial College; Desmond Tutu TB Centre, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa.

Background: Limitations in the sensitivity and accessibility of diagnostic tools for childhood tuberculosis contribute to the substantial gap between estimated cases and cases notified to national tuberculosis programs. Thus, tools to make accurate and rapid clinical diagnoses are necessary to initiate more children on antituberculosis treatment.

Methods: We analyzed data from a prospective cohort of children <13 years being routinely evaluated for pulmonary tuberculosis in Cape Town, South Africa from March 2012 to November 2017. We developed a regression model to describe the contributions of baseline clinical evaluation to the diagnosis of tuberculosis using standardized, retrospective case definitions. We included results from baseline chest radiography and Xpert MTB/RIF to the model to develop an algorithm with at least 90% sensitivity in predicting tuberculosis.

Results: Data from 478 children being evaluated for pulmonary tuberculosis were analyzed (median age: 16.2 months, interquartile range: 9.8-30.9); 242 (50.6%) were retrospectively classified with tuberculosis, of which 104 (43.0%) were bacteriologically-confirmed. The area under the receiver operating characteristic curve for the final model was 0.87. Clinical evidence identified 71.4% of all tuberculosis cases in this cohort, and inclusion of baseline chest radiography results increased the proportion to 89.3%. The algorithm was 90.1% sensitive and 52.1% specific, and maintained a sensitivity of above 90% among children <2 years or with low weight-for-age.

Conclusions: Clinical evidence alone was sufficient to make most clinical antituberculosis treatment decisions. The use of evidence-based algorithms may improve decentralized, rapid treatment-initiation, reducing the global burden of childhood mortality.
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http://dx.doi.org/10.1093/cid/ciab018DOI Listing
January 2021

Trends in Drug Resistance in Childhood Tuberculosis in Cape Town, South Africa.

Pediatr Infect Dis J 2020 07;39(7):604-608

From the Desmond Tutu Tuberculosis Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Background: We determined mycobacterial drug resistance and HIV prevalence among children with bacteriologically confirmed tuberculosis (TB) from March 2013 to February 2017. Results were compared with 5 previous 2-year surveillance studies (2003-2013).

Methods: Prospective surveillance of all bacteriologically confirmed TB in children (0-13 years) completed at Tygerberg Hospital, Cape Town, South Africa. Drug susceptibility testing was done by GenoType MTBDRplus for isoniazid and rifampicin; ofloxacin and amikacin drug susceptibility testing was completed if rifampicin resistance was detected. Xpert MTB/RIF was routinely introduced during this period.

Results: Six hundred sixty-two children, median age 34 months (interquartile range 14-79) had bacteriologically confirmed TB; 587 (88.7%) were culture-confirmed and 75 (11.3%) confirmed by Xpert MTB/RIF only. Of culture-confirmed cases, 509 (86.7%) were pan-susceptible, 47 (8.0%) were multidrug-resistant, 13 (2.2%) were RIF-resistant/INH-susceptible and 18 (3.1%) were INH-resistant/RIF-susceptible. Of Xpert-positive cases, 3/75 (4%), 68/75 (92%) and 4/75 (5%) were RIF-resistant, RIF-susceptible and RIF-indeterminate, respectively. Of 573 (97.6%) children tested, 74 (12.9%) were HIV positive. Compared with previous surveillance periods, RIF mono-resistance increased from 0% to 2.2% (trend test: χ = 7.050, P = 0.0079). HIV prevalence decreased from 29% to 10.6% (trend test: χ = 27.975, P < 0.0001). Of multidrug-resistant cases, 15/47 (32%) were ofloxacin resistant.

Conclusions: The increase in RIF-resistant/INH-susceptible cases and ofloxacin resistance among multidrug-resistant TB cases in children, indicative of recent transmission, is concerning. The prevalence of multidrug-resistant TB remains high in children.
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http://dx.doi.org/10.1097/INF.0000000000002631DOI Listing
July 2020

Specimen Pooling as a Diagnostic Strategy for Microbiologic Confirmation in Children with Intrathoracic Tuberculosis.

Pediatr Infect Dis J 2019 06;38(6):e128-e131

From the Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University.

Three-hundred four young children with suspected pulmonary tuberculosis had a gastric aspirate, induced sputum and nasopharyngeal aspirate collected on each of 2 consecutive weekdays. Specimens collected on the second day were pooled in the laboratory for each child individually. The diagnostic yield by Xpert and culture from pooled specimens was not significantly different to a single gastric aspirate.
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http://dx.doi.org/10.1097/INF.0000000000002240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509014PMC
June 2019

Molecular Detection of Mycobacterium tuberculosis from Stools in Young Children by Use of a Novel Centrifugation-Free Processing Method.

J Clin Microbiol 2018 09 27;56(9). Epub 2018 Aug 27.

Rutgers, New Jersey Medical School, Faculty of Medicine, Newark, New Jersey, USA.

The microbiological diagnosis of tuberculosis (TB) in children is challenging, as it relies on the collection of relatively invasive specimens by trained health care workers, which is not feasible in many settings. is detectable from the stools of children using molecular methods, but processing stool specimens is resource intensive. We evaluated a novel, simple, centrifugation-free processing method for stool specimens for use on the Xpert MTB/RIF assay (Xpert), using two different stool masses: 0.6 g and a swab sample. Two hundred eighty children (median age, 15.5 months; 35 [12.5%] HIV infected) with suspected intrathoracic TB were enrolled from two sites in South Africa. Compared to a single Xpert test on respiratory specimens, the sensitivity of Xpert on stools using the 0.6-g and swab samples was 44.4% (95% confidence interval [CI], 13.7 to 78.8%) for both methods, with a specificity of >99%. The combined sensitivities of two stool tests versus the first respiratory Xpert were 70.0% (95% CI, 34.8 to 93.3) and 50.0% (95% CI, 18.7 to 81.3) for the 0.6-g and swab sample, respectively. Retesting stool specimens with nondeterminate Xpert results improved nondeterminate rates from 9.3% to 3.9% and from 8.6% to 4.3% for 0.6-g and swab samples, respectively. Overall, stool Xpert detected 14/94 (14.9%) children who initiated antituberculosis treatment, while respiratory specimens detected 23/94 (24.5%). This stool processing method is well suited for settings with low capacity for respiratory specimen collection. However, the overall sensitivity to detect confirmed and clinical TB was lower than that of respiratory specimens. More sensitive rapid molecular assays are needed to improve the utility of stools for the diagnosis of intrathoracic TB in children from resource-limited settings.
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http://dx.doi.org/10.1128/JCM.00781-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113478PMC
September 2018

Reply to Drancourt, "Culturing Stools To Detect Mycobacterium tuberculosis".

J Clin Microbiol 2018 05 25;56(5). Epub 2018 Apr 25.

Desmond Tutu TB Centre, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

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http://dx.doi.org/10.1128/JCM.00056-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5925696PMC
May 2018

Complementary surveillance strategies are needed to better characterise the epidemiology, care pathways and treatment outcomes of tuberculosis in children.

BMC Public Health 2018 03 23;18(1):397. Epub 2018 Mar 23.

Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

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 drug-susceptible 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.
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http://dx.doi.org/10.1186/s12889-018-5252-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865349PMC
March 2018

Clinical Evaluation of a Blood Assay to Diagnose Paucibacillary Tuberculosis via Bacterial Antigens.

Clin Chem 2018 05 18;64(5):791-800. Epub 2018 Jan 18.

Virginia G. Piper Biodesign Center for Personalized Diagnostics, The Biodesign Institute, Arizona State University, Tempe, AZ;

Background: The diagnosis of active tuberculosis (TB) cases primarily relies on methods that detect () bacilli or their DNA in patient samples (e.g., mycobacterial culture and Xpert MTB/RIF assays), but these tests have low clinical sensitivity for patients with paucibacillary TB disease. Our goal was to evaluate the clinical performance of a newly developed assay that can rapidly diagnose active TB cases by direct detection of -derived antigens in patients' blood samples.

Methods: Nanoparticle (NanoDisk)-enriched peptides derived from the virulence factors CFP-10 (10-kDa culture factor protein) and ESAT-6 (6-kDa early secretory antigenic target) were analyzed by high-throughput mass spectrometry (MS). Serum from 294 prospectively enrolled Chinese adults were analyzed with this NanoDisk-MS method to evaluate the performance of direct serum antigen measurement as a means for rapid diagnosis of active TB cases.

Results: NanoDisk-MS diagnosed 174 (88.3%) of the study's TB cases, with 95.8% clinical specificity, and with 91.6% and 85.3% clinical sensitivity for culture-positive and culture-negative TB cases, respectively. NanoDisk-MS also exhibited 88% clinical sensitivity for pulmonary and 90% for extrapulmonary TB, exceeding the diagnostic performance of mycobacterial culture for these cases.

Conclusions: Direct detection and quantification of serum antigens by NanoDisk-MS can rapidly and accurately diagnose active TB in adults, independent of disease site or culture status, and outperform -based TB diagnostics.
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http://dx.doi.org/10.1373/clinchem.2017.273698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996152PMC
May 2018

Tuberculous Pericardial Effusions in Children.

J Pediatric Infect Dis Soc 2018 Dec;7(4):346-349

Desmond Tutu TB Centre.

Current data on tuberculous pericardial effusion in children are limited. In this study, the cases of 30 children with tuberculous pericardial effusion were reviewed retrospectively. The prevalence of human immunodeficiency virus and of culture-confirmed tuberculosis was high. Chest radiography provided lower diagnostic sensitivity than sonography but detected all large and complicated effusions. Outcomes were generally good, and residual complications were mainly due to comorbidity.
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http://dx.doi.org/10.1093/jpids/pix087DOI Listing
December 2018

Stool Culture for Diagnosis of Pulmonary Tuberculosis in Children.

J Clin Microbiol 2017 12 13;55(12):3355-3365. Epub 2017 Sep 13.

Desmond Tutu TB Centre, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Bacteriological confirmation of 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 (-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 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 detection in children with intrathoracic TB. Reducing culture contamination through improved laboratory protocols may enable more reliable estimates of its diagnostic utility.
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http://dx.doi.org/10.1128/JCM.00801-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703802PMC
December 2017

Xpert MTB/RIF on Stool Is Useful for the Rapid Diagnosis of Tuberculosis in Young Children With Severe Pulmonary Disease.

Pediatr Infect Dis J 2017 Sep;36(9):837-843

From the *Desmond Tutu TB Centre, Department of Paediatrics and Child Health, †DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, MRC Centre for Tuberculosis Research, Division of Medical Physiology, Faculty of Medicine and Health Sciences, ‡Department of Medical Microbiology and National Health Laboratory Service, §DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, US/SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, and ¶Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Background: Tuberculosis (TB) continues to result in high morbidity and mortality in children from resource-limited settings. Diagnostic challenges, including resource-intense sputum collection methods and insensitive diagnostic tests, contribute to diagnostic delay and poor outcomes in children. We evaluated the diagnostic utility of stool Xpert MTB/RIF (Xpert) compared with bacteriologic confirmation (combination of Xpert and culture of respiratory samples).

Methods: In a hospital-based study in Cape Town, South Africa, we enrolled children younger than 13 years of age with suspected pulmonary TB from April 2012 to August 2015. Standard clinical investigations included tuberculin skin test, chest radiograph and HIV testing. Respiratory samples for smear microscopy, Xpert and liquid culture included gastric aspirates, induced sputum, nasopharyngeal aspirates and expectorated sputum. One stool sample per child was collected and tested using Xpert.

Results: Of 379 children enrolled (median age, 15.9 months, 13.7% HIV infected), 73 (19.3%) had bacteriologically confirmed TB. The sensitivity and specificity of stool Xpert versus overall bacteriologic confirmation were 31.9% [95% confidence interval (CI): 21.84%-44.50%] and 99.7% (95% CI: 98.2%-100%), respectively. A total of 23/51 (45.1%) children with bacteriologically confirmed TB with severe disease were stool Xpert positive. Cavities on chest radiograph were associated with Xpert stool positivity regardless of age and other relevant factors [odds ratios (OR) 7.05; 95% CI: 2.16-22.98; P = 0.001].

Conclusions: Stool Xpert can rapidly confirm TB in children who present with radiologic findings suggestive of severe TB. In resource-limited settings where children frequently present with advanced disease, Xpert on stool samples could improve access to rapid diagnostic confirmation and appropriate treatment.
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http://dx.doi.org/10.1097/INF.0000000000001563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558052PMC
September 2017

Editorial Commentary: Improving Children's Access to New Tuberculosis Diagnostic Tools Starts With the Collection of Appropriate Specimens.

Clin Infect Dis 2016 May 7;62(9):1169-71. Epub 2016 Feb 7.

Department of Paediatrics and Child Health, Desmond Tutu TB Centre, Stellenbosch University, Cape Town, South Africa.

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http://dx.doi.org/10.1093/cid/ciw042DOI Listing
May 2016

Direct detection of Mycobacterium tuberculosis in sputum: A validation study using solid phase extraction-gas chromatography-mass spectrometry.

J Chromatogr B Analyt Technol Biomed Life Sci 2016 Feb 19;1012-1013:50-4. Epub 2015 Dec 19.

University of Amsterdam, Van 't Hoff Institute for Molecular Sciences, Analytical Chemistry Group, P.O. Box 94157, 1090 GD Amsterdam, The Netherlands.

Tuberculosis (TB) remains a worldwide health problem, especially in developing countries. Correct identification of Mycobacterium tuberculosis (MTB) infection is extremely important for providing appropriate treatment and care to patients. Here we describe a solid phase extraction-gas chromatography-mass spectrometry method (SPE-THM-GC-MS) for the detection of five biomarkers for M. tuberculosis. The method for classification is developed and validated through the analysis of 112 sputum samples from patients suspected of having TB. Twenty of twenty-five MTB culture-positive sputum samples were correctly classified as positive by our improved SPE-THM-GC-MS method. Eighty-five of eighty-seven MTB culture-negative samples were also negative by SPE-THM-GC-MS. The overall sensitivity of the new SPE-THM-GC-MS method is 80% (20/25) and the specificity is 98% (85/87) compared with culture. The method proved to be reliable and, although complex in principle, easy to operate due to the high degree of automation.
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http://dx.doi.org/10.1016/j.jchromb.2015.12.023DOI Listing
February 2016

Direct detection of Mycobacterium tuberculosis in sputum using combined solid phase extraction-gas chromatography-mass spectrometry.

J Chromatogr B Analyt Technol Biomed Life Sci 2015 Apr 9;986-987:115-22. Epub 2015 Feb 9.

Analytical Chemistry & Forensic Science, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands.

Recently, thermally-assisted hydrolysis and methylation followed by gas chromatography-mass spectrometry (THM-GC-MS) in combination with chemometrics has been used to develop a 20-compound model for fast differentiation of Mycobacterium tuberculosis (MTB) from Non-tuberculous mycobacteria (NTM) in bacterial cultures. This model provided better than 95% accuracy. In our current work a hexane/methanol/water extraction followed by a solid phase extraction (SPE) clean-up procedure was developed for use before THM-GC-MS, to make the test suitable for the identification of mycobacteria in sputum. The 20 biomarker model had to be adapted since many compounds were also found in the sputum of non-tuberculosis patients. An algorithm was established based on tuberculostearic acid, hexacosanoic acid and mycoserosates. The detection limit of the method was approximately 1×10(4) bacteria/mL sputum. Sputum specimens from 32 patients from South Africa who were suspected of having tuberculosis were blindly tested using the new method. Eight of the nine culture-positive sputum specimens were detected by the new SPE-THM-GC-MS method, resulting in a sensitivity of 89%. The specimen that was missed by the new method was also microscopy negative. The specificity of the test was 100%; all 23 microscopy- and culture-negative specimens were correctly identified as negative by SPE-THM-GC-MS.
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http://dx.doi.org/10.1016/j.jchromb.2015.01.045DOI Listing
April 2015

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

Arch Dis Child 2014 Nov 17;99(11):998-1003. Epub 2014 Jun 17.

Department of Paediatrics and Child Health, Tygerberg Academic Hospital, Stellenbosch University, Cape Town, South Africa.

Background: Early initiation of antiretroviral therapy (ART) in HIV-infected infants reduces mortality and opportunistic infections including tuberculosis (TB). However, young HIV-infected children remain at high risk of TB disease following mycobacterial infection. We document the spectrum of TB disease in HIV-infected children <2 years of age on ART.

Methods: Retrospective cohort study; records of children <2 years of age initiating routine ART at Tygerberg Children's Hospital, Cape Town, January 2003-December 2010 were reviewed. Clinical data at ART initiation (baseline) and TB episodes after ART initiation, to June 2012, were recorded. TB immune reconstitution syndrome (TB-IRIS) and incident TB were defined as TB diagnosed within 3 months, and >3 months after, ART initiation respectively. Baseline characteristics were compared in children with TB-IRIS and those with incident TB.

Results: In 494 children, median follow-up time on ART was 10.7 months. Fifty-five TB treatment episodes occurred after ART initiation: 23 (42%) TB-IRIS (incidence 21.9/100 person years (py)) and 32 (58%) incident TB (incidence 3.9/100 py). Children with TB-IRIS and those with incident TB had similar baseline characteristics. Eight of 10 cases of extrapulmonary TB were severe: 4 IRIS (2 meningitis, 1 disseminated, 1 pericarditis) and 4 incident cases (1 each miliary, meningitis, pericarditis and spinal). Fifty-one children (10%) died (mortality rate 5.96/100 py). Starting ART at <1 year of age approached significance as a risk factor for TB-IRIS (adjusted OR (AOR) 8.64, p=0.06); weight-for-age Z score <-2 predicted death (AOR 6.37, p<0.001).

Conclusions: Severe TB manifestations were observed among young HIV-infected children on ART.
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http://dx.doi.org/10.1136/archdischild-2013-305509DOI Listing
November 2014

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

Pediatr Pulmonol 2014 Nov 11;49(11):1133-7. Epub 2013 Dec 11.

Faculty of Medicine and Health Sciences, Department of Paediatrics and Child Health, Desmond Tutu TB Centre, Stellenbosch University, Cape Town, South Africa.

Background: Children with complicated intrathoracic tuberculosis (TB) require rapid confirmation of TB diagnosis and of drug susceptibility to institute appropriate therapy. In a pilot study, we evaluated the feasibility and potential utility of GeneXpert (Xpert) on bronchoalveolar lavage (BAL) samples in children undergoing routine diagnostic bronchoscopy.

Methods: We included children <13 years of age undergoing bronchoscopy for suspected complicated intrathoracic TB at Tygerberg Children's Hospital, October 1, 2012-May 15, 2013. A minimum of two respiratory specimens in addition to BAL were obtained from each child. In addition to fluorescent smear microscopy and automated liquid culture performed on all samples, BAL samples were analyzed by Xpert. Drug susceptibility was confirmed by GenoType(®) MTBDRplus.

Results: Fourteen children (2 HIV positive, median age 16 months) were included. The Mantoux tuberculin skin test was positive in 11. On chest radiograph, six children had expansile pneumonia and nine had airway compression (one had both). The median duration of TB treatment before bronchoscopy was 8 days. TB was confirmed by either culture or Xpert from any sample in 11 (78%) children. Among 9/14 (64%) cases confirmed by culture, BAL Xpert was positive in 7 (78% sensitivity); in addition, Xpert confirmed 2 cases who had negative culture (14% additional diagnostic yield). Two drug resistant cases were identified: one by BAL Xpert and one from genotypic testing of a culture from gastric aspirate. All children were initiated on anti-TB treatment and responded well to therapy.

Conclusion: BAL Xpert resulted in additional diagnostic yield and also in the rapid detection of drug resistance in children with complicated intrathoracic TB. The clinical impact of this modality should be further evaluated in children.
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http://dx.doi.org/10.1002/ppul.22970DOI Listing
November 2014

Validation of biomarkers for distinguishing Mycobacterium tuberculosis from non-tuberculous mycobacteria using gas chromatography-mass spectrometry and chemometrics.

PLoS One 2013 17;8(10):e76263. Epub 2013 Oct 17.

Analytical Chemistry and Forensic Science, University of Amsterdam, Amsterdam, The Netherlands.

Tuberculosis (TB) remains a major international health problem. Rapid differentiation of Mycobacterium tuberculosis complex (MTB) from non-tuberculous mycobacteria (NTM) is critical for decisions regarding patient management and choice of therapeutic regimen. Recently we developed a 20-compound model to distinguish between MTB and NTM. It is based on thermally assisted hydrolysis and methylation gas chromatography-mass spectrometry and partial least square discriminant analysis. Here we report the validation of this model with two independent sample sets, one consisting of 39 MTB and 17 NTM isolates from the Netherlands, the other comprising 103 isolates (91 MTB and 12 NTM) from Stellenbosch, Cape Town, South Africa. All the MTB strains in the 56 Dutch samples were correctly identified and the model had a sensitivity of 100% and a specificity of 94%. For the South African samples the model had a sensitivity of 88% and specificity of 100%. Based on our model, we have developed a new decision-tree that allows the differentiation of MTB from NTM with 100% accuracy. Encouraged by these findings we will proceed with the development of a simple, rapid, affordable, high-throughput test to identify MTB directly in sputum.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0076263PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3798606PMC
August 2014

Utility of host markers detected in Quantiferon supernatants for the diagnosis of tuberculosis in children in a high-burden setting.

PLoS One 2013 15;8(5):e64226. Epub 2013 May 15.

DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.

Background: 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-α2, 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-α2, 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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0064226PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655018PMC
January 2014

Antiretroviral regimens containing a single protease inhibitor increase risk of virologic failure in young HIV-infected children.

Pediatr Infect Dis J 2013 Apr;32(4):361-3

Department of Paediatrics and Child Health, Desmond Tutu TB Centre, Stellenbosch University, South Africa.

Rifampin-based tuberculosis treatment can cause subtherapeutic concentrations of protease inhibitors and virologic failure in children receiving antiretroviral therapy. Among 217 children on antiretroviral therapy, tuberculosis cotreatment (in 78) was associated with virologic failure. Ritonavir-based single protease inhibitor antiretroviral therapy regimen predicted virologic failure (adjusted odds ratio 3.7, 95% confidence interval 1.5-8.9, P = 0.004) on multivariate analysis.
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http://dx.doi.org/10.1097/INF.0b013e318279c800DOI Listing
April 2013

Clinical presentation and outcome of tuberculosis in human immunodeficiency virus infected children on anti-retroviral therapy.

BMC Pediatr 2008 Jan 11;8. Epub 2008 Jan 11.

Department of Pediatrics and Child Health, Faculty of Health Sciences, Stellenbosch University, Cape Town, South Africa.

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.
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http://dx.doi.org/10.1186/1471-2431-8-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2246130PMC
January 2008

Meningococcal purpura fulminans treated with medicinal leeches.

Pediatr Crit Care Med 2006 Sep;7(5):476-8

Department of Paediatrics and Child Health, University of Stellenbosch, Tygerberg Children's Hospital, Tygerberg, South Africa.

Introduction: Meningococcal septicemia remains one of the most common infectious causes of admission to a pediatric intensive care unit. Numerous treatment strategies aimed at the thromboembolic complications inducing purpura fulminans and limb/digital ischemia have been attempted, with variable results. The successful use of medicinal leeches for pneumococcal purpura fulminans has been described, and we present a similar case of meningococcal purpura fulminans.

Patient And Intervention: A 5-wk-old female infant with meningococcal meningitis and septicemia and progressive purpura fulminans of the left hand was treated with medicinal leeches. Medicinal leeches were applied to the left dorsal hand on a daily basis for 4 consecutive days.

Result: The swelling and limited functionality visibly improved after 48 hrs, and by 120 hrs, perfusion in the distal phalanges of the thumb and middle finger was evident. Reperfusion of the distal phalanges was not fully sustained, and at 6 wks the plastic surgery department debrided the distal phalanges of her left hand, excluding the thumb. She fully recovered from the meningococcal septicemic shock; the functionality of her left thumb was preserved, and she has limited functionality of her left hand.

Conclusion: The unique combination of salivary products in leech therapy has theoretical benefits and requires future study.
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http://dx.doi.org/10.1097/01.PCC.0000235422.23812.B4DOI Listing
September 2006