Diagnosis of Childhood Tuberculosis and Host RNA Expression in Africa

Abstract

BACKGROUND Improved diagnostic tests for tuberculosis in children are needed. We hypothesized that transcriptional signatures of host blood could be used to distinguish tuberculosis from other diseases in African children who either were or were not infected with the human immunodeficiency virus (HIV). METHODS The study population comprised prospective cohorts of children who were undergoing evaluation for suspected tuberculosis in South Africa (655 children), Malawi (701 children), and Kenya (1599 children). Patients were assigned to groups according to whether the diagnosis was culture-confirmed tuberculosis, culture-negative tuberculosis, diseases other than tuberculosis, or latent tuberculosis infection. Diagnostic signatures distinguishing tuberculosis from other diseases and from latent tuberculosis infection were identified from genomewide analysis of RNA expression in host blood. RESULTS We identified a 51-transcript signature distinguishing tuberculosis from other diseases in the South African and Malawian children (the discovery cohort). In the Kenyan children (the validation cohort), a risk score based on the signature for tuberculosis and for diseases other than tuberculosis showed a sensitivity of 82.9% (95% confidence interval [CI], 68.6 to 94.3) and a specificity of 83.6% (95% CI, 74.6 to 92.7) for the diagnosis of culture-confirmed tuberculosis. Among patients with cultures negative for Mycobacterium tuberculosis who were treated for tuberculosis (those with highly probable, probable, or possible cases of tuberculosis), the estimated sensitivity was 62.5 to 82.3%, 42.1 to 80.8%, and 35.3 to 79.6%, respectively, for different estimates of actual tuberculosis in the groups. In comparison, the sensitivity of the Xpert MTB/RIF assay for molecular detection of M. tuberculosis DNA in cases of culture-confirmed tuberculosis was 54.3% (95% CI, 37.1 to 68.6), and the sensitivity in highly probable, probable, or possible cases was an estimated 25.0 to 35.7%, 5.3 to 13.3%, and 0%, respectively; the specificity of the assay was 100%. CONCLUSIONS RNA expression signatures provided data that helped distinguish tuberculosis from other diseases in African children with and those without HIV infection. (Funded by the European Union Action for Diseases of Poverty Program and others).

Clinical Immunology and Multiplex Biomarkers of Human Tuberculosis

“…A disease risk score was developed that can now be developed into a simple test format suitable for use in HIV-infected TB populations. A more recent study extended this work also to TB-infected infants, with similar results in terms of the identification of useful diagnostic TB disease mRNA biosignature (Anderson et al 2014). Prospective studies using such tests are now needed to validate their actual performance.…”

Blood Transcriptional Biomarkers for Active Tuberculosis among Patients in the United States: a Case-Control Study with Systematic Cross-Classifier Evaluation

“…Selected sets of mRNA transcripts have been used in prediction models to classify patient samples as having active TB or not (5)(6)(7)(8)(9)(10)(11). In early phase studies (12), blood transcriptional classifiers have shown promise for active TB diagnosis (3,10,11,13,14) and for monitoring treatment response (15).…”

Potential Cost-effectiveness of Early Identification of Hospital-acquired Infection in Critically Ill Patients

“…Recent advances in systems biology and computational biology have created new opportunities. For example, gene-expression analysis has been used to differentiate active pulmonary tuberculosis from both latent tuberculosis and nontuberculous disease (36)(37)(38). Test characteristics were superior to currently available pathogen-detection techniques.…”