Development of treatment-decision algorithms for children evaluated for pulmonary tuberculosis: an individual participant data meta-analysis.

BACKGROUND: Many children with pulmonary tuberculosis remain undiagnosed and untreated with related high morbidity and mortality. Recent advances in childhood tuberculosis algorithm development have incorporated prediction modelling, but studies so far have been small and localised, with limited generalisability. We aimed to evaluate the performance of currently used diagnostic algorithms and to use prediction modelling to develop evidence-based algorithms to assist in tuberculosis treatment decision making for children presenting to primary health-care centres. METHODS: For this meta-analysis, we identified individual participant data from a WHO public call for data on the management of tuberculosis in children and adolescents and referral from childhood tuberculosis experts. We included studies that prospectively recruited consecutive participants younger than 10 years attending health-care centres in countries with a high tuberculosis incidence for clinical evaluation of pulmonary tuberculosis. We collated individual participant data including clinical, bacteriological, and radiological information and a standardised reference classification of pulmonary tuberculosis. Using this dataset, we first retrospectively evaluated the performance of several existing treatment-decision algorithms. We then used the data to develop two multivariable prediction models that included features used in clinical evaluation of pulmonary tuberculosis-one with chest x-ray features and one without-and we investigated each model's generalisability using internal-external cross-validation. The parameter coefficient estimates of the two models were scaled into two scoring systems to classify tuberculosis with a prespecified sensitivity target. The two scoring systems were used to develop two pragmatic, treatment-decision algorithms for use in primary health-care settings. FINDINGS: Of 4718 children from 13 studies from 12 countries, 1811 (38·4%) were classified as having pulmonary tuberculosis: 541 (29·9%) bacteriologically confirmed and 1270 (70·1%) unconfirmed. Existing treatment-decision algorithms had highly variable diagnostic performance. The scoring system derived from the prediction model that included clinical features and features from chest x-ray had a combined sensitivity of 0·86 [95% CI 0·68-0·94] and specificity of 0·37 [0·15-0·66] against a composite reference standard. The scoring system derived from the model that included only clinical features had a combined sensitivity of 0·84 [95% CI 0·66-0·93] and specificity of 0·30 [0·13-0·56] against a composite reference standard. The scoring system from each model was placed after triage steps, including assessment of illness acuity and risk of poor tuberculosis-related outcomes, to develop treatment-decision algorithms. INTERPRETATION: We adopted an evidence-based approach to develop pragmatic algorithms to guide tuberculosis treatment decisions in children, irrespective of the resources locally available. This approach will empower health workers in primary health-care settings with high tuberculosis incidence and limited resources to initiate tuberculosis treatment in children to improve access to care and reduce tuberculosis-related mortality. These algorithms have been included in the operational handbook accompanying the latest WHO guidelines on the management of tuberculosis in children and adolescents. Future prospective evaluation of algorithms, including those developed in this work, is necessary to investigate clinical performance. FUNDING: WHO, US National Institutes of Health.

Tuberculosis Diagnosis in HIV-Infected Children: Comparison of the 2012 and 2015 Clinical Case Definitions for Classification of Intrathoracic Tuberculosis Disease.

BACKGROUND: There is no gold standard for tuberculosis diagnosis in children. Clinical Case Definitions for Classification of Intrathoracic Tuberculosis in Children were proposed by international experts in 2012 and updated in 2015. We aimed to compare the 2012 and 2015 Clinical Case Definitions in HIV-infected children with suspected tuberculosis. METHODS: We enrolled HIV-infected children with suspected tuberculosis in Burkina Faso, Cambodia, Cameroon, and Vietnam (ANRS [Agence Nationale de Recherches sur le SIDA et les hépatites virales] 12229 PAANTHER [Pediatric Asian African Network for Tuberculosis and HIV Research] 01 Study). We classified children using the 2012 and 2015 Case Definitions considering as tuberculosis cases those with confirmed tuberculosis and those with probable and unconfirmed tuberculosis in the 2012 and the 2015 classifications, respectively. We assessed agreement between both classifications. RESULTS: Of 438 children enrolled, 197 (45.0%) children were classified as tuberculosis (45 confirmed, 152 probable) using the 2012 Case Definition and 251 (57.3%) were classified as tuberculosis (55 confirmed, 196 unconfirmed) using the 2015 classification. Inter-classification agreement for tuberculosis diagnosis was 364/438, 83.1%, with a kappa statistic of 0.667 (95% confidence interval 0.598-0.736). Of 152 children with probable tuberculosis (2012), 142 (93.4%) were considered as tuberculosis by the 2015 version and 10 (6.6%) as unlikely tuberculosis including 9 with spontaneous clinical improvement. Of 132 possible tuberculosis (2012), 58 (43.9%) were reclassified as tuberculosis (2015). CONCLUSIONS: Agreement between the 2 versions of the Case Definition was substantial but more children were considered as tuberculosis using the 2015 version. Spontaneous symptom resolution reinforces both confidence in the "unlikely" category as being children without tuberculosis and the importance of the clinician's treatment decision in the study.

A Treatment-Decision Score for HIV-Infected Children With Suspected Tuberculosis.

BACKGROUND: Diagnosis of tuberculosis should be improved in children infected with HIV to reduce mortality. We developed prediction scores to guide antituberculosis treatment decision in HIV-infected children with suspected tuberculosis. METHODS: HIV-infected children with suspected tuberculosis enrolled in Burkina Faso, Cambodia, Cameroon, and Vietnam (ANRS 12229 PAANTHER 01 Study), underwent clinical assessment, chest radiography, Quantiferon Gold In-Tube (QFT), abdominal ultrasonography, and sample collection for microbiology, including Xpert MTB/RIF (Xpert). We developed 4 tuberculosis diagnostic models using logistic regression: (1) all predictors included, (2) QFT excluded, (3) ultrasonography excluded, and (4) QFT and ultrasonography excluded. We internally validated the models using resampling. We built a score on the basis of the model with the best area under the receiver operating characteristic curve and parsimony. RESULTS: A total of 438 children were enrolled in the study; 251 (57.3%) had tuberculosis, including 55 (12.6%) with culture- or Xpert-confirmed tuberculosis. The final 4 models included Xpert, fever lasting >2 weeks, unremitting cough, hemoptysis and weight loss in the past 4 weeks, contact with a patient with smear-positive tuberculosis, tachycardia, miliary tuberculosis, alveolar opacities, and lymph nodes on the chest radiograph, together with abdominal lymph nodes on the ultrasound and QFT results. The areas under the receiver operating characteristic curves were 0.866, 0.861, 0.850, and 0.846, for models 1, 2, 3, and 4, respectively. The score developed on model 2 had a sensitivity of 88.6% and a specificity of 61.2% for a tuberculosis diagnosis. CONCLUSIONS: Our score had a good diagnostic performance. Used in an algorithm, it should enable prompt treatment decision in children with suspected tuberculosis and a high mortality risk, thus contributing to significant public health benefits.

Isolation of Nontuberculous Mycobacteria in Southeast Asian and African Human Immunodeficiency Virus-infected Children With Suspected Tuberculosis.

We enrolled 427 human immunodeficiency virus-infected children (median age, 7.3 years), 59.2% severely immunodeficient, with suspected tuberculosis in Southeast Asian and African settings. Nontuberculous mycobacteria were isolated in 46 children (10.8%); 45.7% of isolates were Mycobacterium avium complex. Southeast Asian origin, age 5-9 years, and severe immunodeficiency were independently associated with nontuberculous mycobacteria isolation. CLINICAL TRIALS REGISTRATION: NCT01331811.

Mortality and its determinants in antiretroviral treatment-naive HIV-infected children with suspected tuberculosis: an observational cohort study.

BACKGROUND: Tuberculosis is a major cause of morbidity and mortality in HIV-infected children, but is difficult to diagnose. We studied mortality and its determinants in antiretroviral treatment (ART)-naive HIV-infected children presenting with suspected tuberculosis. METHODS: In this observational cohort study, HIV-infected children aged 13 years or younger with suspected tuberculosis were followed up for 6 months as part of the ANRS 12229 PAANTHER 01 cohort in eight hospitals in four countries (Burkina Faso, Cambodia, Cameroon, and Vietnam). Children started ART and antituberculosis treatment at the clinician's discretion and were retrospectively classified into one of three groups by tuberculosis documentation: confirmed by culture or Xpert MTB/RIF, unconfirmed, and unlikely. We assessed mortality and associated factors using Kaplan-Meier methods and Cox proportional hazard models. The ANRS 12229 PAANTHER 01 study is registered at ClinicalTrials.gov, number NCT01331811. FINDINGS: 266 (61%) of 438 children enrolled in the study between April 27, 2011, and May 31, 2014, were ART-naive and included in the analysis (40 had confirmed tuberculosis, 119 unconfirmed tuberculosis, and 107 unlikely tuberculosis). 112·5 person-years of follow-up were available. 154 children (58%) started antituberculosis treatment and 212 (80%) started ART. 50 children (19%) died. Mortality by 6 months was higher in children with confirmed tuberculosis (14 deaths; 2 month survival probability 65·0% [95% CI 50·2-79·8]) compared with unconfirmed tuberculosis (19 deaths; 83·5% [76·8-90·3]) and unlikely tuberculosis (17 deaths; 83·5% [76·3-90·7]; log-rank p=0·0141) and was lower in children with confirmed or unconfirmed tuberculosis who started antituberculosis treatment (p<0·0001 for both). In a multivariate analysis, ART started during the first month of follow-up (hazard ratio 0·08; 95% CI 0·01-0·67), confirmed tuberculosis (6·33; 2·15-18·64), young age (5·90; 2·02-17·19), CD4 less than 10% (2·63; 1·25-5·53), miliary features (4·08; 1·56-10·66), and elevated serum transaminases (4·40; 1·82-10·65) were all independently associated with mortality. INTERPRETATION: In our cohort, mortality was high in the first 6 months after suspicion of tuberculosis in ART-naive children. ART should be started early, particularly in children with factors associated with high mortality. Documented or empirical tuberculosis treatment decision should be accelerated to reduce mortality and allow early ART initiation. FUNDING: ANRS and Fondation Total.

Performance of Xpert MTB/RIF and Alternative Specimen Collection Methods for the Diagnosis of Tuberculosis in HIV-Infected Children.

BACKGROUND: The diagnosis of tuberculosis in human immunodeficiency virus (HIV)-infected children is challenging. We assessed the performance of alternative specimen collection methods for tuberculosis diagnosis in HIV-infected children using Xpert MTB/RIF (Xpert). METHODS: HIV-infected children aged ≤13 years with suspected intrathoracic tuberculosis were enrolled in 8 hospitals in Burkina Faso, Cambodia, Cameroon, and Vietnam. Gastric aspirates were taken for children aged <10 years and expectorated sputum samples were taken for children aged ≥10 years (standard samples); nasopharyngeal aspirate and stool were taken for all children, and a string test was performed if the child was aged ≥4 years (alternative samples). All samples were tested with Xpert. The diagnostic accuracy of Xpert for culture-confirmed tuberculosis was analyzed in intention-to-diagnose and per-protocol approaches. RESULTS: Of 281 children enrolled, 272 (96.8%) had ≥1 specimen tested with Xpert (intention-to-diagnose population), and 179 (63.5%) had all samples tested with Xpert (per-protocol population). Tuberculosis was culture-confirmed in 29/272 (10.7%) children. Intention-to-diagnose sensitivities of Xpert performed on all, standard, and alternative samples were 79.3% (95% confidence interval [CI], 60.3-92.0), 72.4% (95% CI, 52.8-87.3), and 75.9% (95% CI, 56.5-89.7), respectively. Specificities were ≥97.5%. Xpert combined on nasopharyngeal aspirate and stool had intention-to-diagnose and per-protocol sensitivities of 75.9% (95% CI, 56.5-89.7) and 75.0% (95% CI, 47.6-92.7), respectively. CONCLUSIONS: The combination of nasopharyngeal aspirate and stool sample is a promising alternative to methods usually recommended by national programs. Xpert performed on respiratory and stools samples enables rapid confirmation of tuberculosis diagnosis in HIV-infected children. CLINICAL TRIALS REGISTRATION: The ANRS (Agence Nationale de Recherche sur le Sida) 12229 PAANTHER (Pediatric Asian African Network for Tuberculosis and HIV Research) 01 study is registered at ClinicalTrials.gov (NCT01331811).

The long-term outcomes of antiretroviral treatment initiated with mono or dual nucleoside reverse transcriptase inhibitors in HIV-1-infected children: an Asian observational study.

After a median of 115.9 months of follow-up, 90% of 206 HIV-1-infected children in a cohort in Asia who initiated antiretroviral treatment (ART) with mono or dual nucleoside reverse transcriptase inhibitors were alive and had comparable immunological and virological outcomes as compared to the 1,915 children who had started with highly active antiretroviral regimens. However, these children had higher rates of treatment-related adverse events, opportunistic infections, and cumulative mortality, and were more likely to require protease inhibitor-containing regimens or other more novel ART-based regimens.

Weight as predictors of clinical progression and treatment failure: results from the TREAT Asia Pediatric HIV Observational Database.

OBJECTIVE: To evaluate the value of time-updated weight and height in predicting clinical progression, and immunological and virological failure in children receiving combination antiretroviral therapy (cART). METHODS: We used Cox regression to analyze data of a cohort of Asian children. RESULTS: A total of 2608 children were included; median age at cART was 5.7 years. Time-updated weight for age z score < -3 was associated with mortality (P < 0.001) independent of CD4% and < -2 was associated with immunological failure (P ≤ 0.03) independent of age at cART. CONCLUSIONS: Weight monitoring provides useful data to inform clinical management of children on cART in resource-limited settings.