Elisabetta Walters

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

BackgroundThe 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.MethodsWe performed a comprehensive file review of all children who commenced HAART at Tygerberg Childrens Hospital from January 2003 through December 2005.ResultsData 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%).ConclusionWe 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.

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

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.

Novel application of NIH case definitions in a paediatric tuberculosis contact investigation study.

BACKGROUNDnInternational (National Institutes of Health [NIH]) case definitions have been proposed for paediatric tuberculosis (TB) diagnostic studies. The relevance of these definitions for contact tracing studies is unknown.nnnMETHODSnWe developed case definitions for a community-based contact tracing diagnostic study. We compare disease certainty using protocol-defined and NIH case definitions and describe TB disease spectrum and severity.nnnRESULTSnThere were 111 potential disease episodes in 109 (21% human immunodeficiency virus [HIV] infected) of 1093 children enrolled. Based on NIH definitions, there were 8 confirmed, 12 probable, 17 possible and 3 unlikely TB and 2 non-TB episodes. Using protocol case definitions, there were 23 episodes of confirmed, 36 probable, 27 possible and 0 unlikely TB and 21 non-TB. Of 111 potential episodes, 69 were unclassifiable using the NIH definition, while 4 were unclassifiable using the protocol definition. Agreement between definitions was 0.30 (95%CI 0.23-0.38). There were 62 episodes (72%) of non-severe and 24 (28%) of severe TB.nnnCONCLUSIONSnThe NIH definition had limited applicability to household contact studies, despite the wide spectrum of disease observed. Further research is needed to develop case definitions relevant to different research settings, including contact investigation to capture the wide spectrum of paediatric TB in clinical research.

Stool Culture for Diagnosis of Pulmonary Tuberculosis in Children

ABSTRACT 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.

Antiretroviral Regimens Containing a Single Protease Inhibitor Increase Risk of Virologic Failure in Young HIV-infected Children

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.

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

BACKGROUNDnThe diagnosis of active tuberculosis (TB) cases primarily relies on methods that detect Mycobacterium tuberculosis (Mtb) 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 Mtb-derived antigens in patients blood samples.nnnMETHODSnNanoparticle (NanoDisk)-enriched peptides derived from the Mtb 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 Mtb antigen measurement as a means for rapid diagnosis of active TB cases.nnnRESULTSnNanoDisk-MS diagnosed 174 (88.3%) of the studys 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.nnnCONCLUSIONSnDirect detection and quantification of serum Mtb antigens by NanoDisk-MS can rapidly and accurately diagnose active TB in adults, independent of disease site or culture status, and outperform Mycobacterium-based TB diagnostics.

Timing of HIV diagnosis in children with tuberculosis managed at a referral hospital in Cape Town, South Africa

SETTINGnTygerberg Hospital, Western Cape Province, Cape Town, South Africa.nnnOBJECTIVEnTo investigate the prevalence of and factors associated with simultaneous tuberculosis (TB) and human immunodeficiency virus (HIV) diagnoses in children.nnnDESIGNnRetrospective cohort study in TB-HIV co-infected children aged <13 years admitted to Tygerberg Hospital in 2012. Data were collected from medical records, laboratory results and electronic TB treatment registers. A simultaneous TB-HIV diagnosis was defined as an HIV diagnosis made within 7 days before or after a diagnosis of TB.nnnRESULTSnOf 88 children with TB-HIV co-infection, 37 (42%) had a simultaneous TB-HIV diagnosis; 51 children had been known to have HIV before their TB diagnosis. Interruption of antiretroviral therapy (ART) was reported in 9/32 (28%) children with known HIV infection at TB diagnosis, while missed opportunities for ART initiation were identified in 8/19 (42%) ART-naïve children. Simultaneous TB-HIV diagnosis was more likely if maternal HIV infection was unknown at the time of the childs birth (OR 2.7, 95%CI 1.0-7.2), and was associated with unfavourable TB treatment outcomes (OR 5.9, 95%CI 1.4-25.2).nnnCONCLUSIONnTB diagnosis provides an important opportunity to test children for HIV. Missed opportunities for HIV prevention, earlier diagnosis and ART initiation were identified.

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

BackgroundTuberculosis (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.MethodsWe conducted a prospective cohort study including all children (<u200913xa0years) 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.ResultsDuring 2012, 395 children (180 [45.6%] <u20092xa0years) 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 <−u20093. 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).ConclusionsThe 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.

Tuberculous Pericardial Effusions in Children

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.