What steps do we need to take to improve diagnosis of tuberculosis in children?

Abstract

Tuberculosis still represents a big global public health challenge. The diagnosis of tuberculosis and the differentiation between active and latent tuberculosis remain difficult, particularly in childhood, because of the lack of a gold standard test for diagnosis. In the last decade, novel diagnostic assays have been developed. Among immunologic tests, new assays based on the measurement of different cytokines released by specific T cells in response to Mycobacterium tuberculosis antigens, other than INF-γ, have been investigated. Promising results rely on nucleic acid amplification techniques, also able to detect drugs resistance. Innovative research fields studied the modifications of CD27 expression in T cells as well as different host gene expression in response to M. tuberculosis. Further studies are needed to assess the diagnostic value and the accuracy of these new assays.

Keywords:

• children
• diagnosis
• IGRA
• IP-10
• Mycobacterium tuberculosis
• tuberculosis
• Xpert MTB/RIF

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues

• The diagnosis of latent and active tuberculosis (TB) in children is often difficult and represents a challenge for pediatricians and healthcare workers.

• Antigens, other than ESAT-6, CFP-10 and TB7.7, have been studied in order to generate a powerful cytokine response. T-cell responses to Rv3873 and Rv3878 seem to predict the progression to active TB, whereas T-cell responses to Rv3873 and Rv3879c might be early markers of TB exposure.

• Biomarkers other than IFN-γ are known to be expressed after antigens stimulation in IGRAs supernatant. The most promising one is the IFN-γ-inducible protein-10, which seems to be not influenced by age. IL-2 levels have been also studied in children and seem to be an useful marker in differentiating active and latent TB.

• Recently, an interesting research field studied host response gene expression specific for different pathogens. The transcriptional RNA, detected in peripheral blood using various techniques, was shown to distinguish TB from other diseases but also active TB from latent infection.

• The analysis of immunological modification of T cells seems to be a promising prospective research field. Assays on T-cell phenotype in response to Mycobacterium tuberculosis antigens have been assessed; measuring on fresh whole blood samples the CD27 phenotype of CD4 T cells.

• A low-cost liquid culture based method, known as microscopic observation drug susceptibility, has been evaluated in developing countries, showing a good sensitivity and specificity compared with other liquid and solid culture types.

• Nucleic acid amplification techniques, such as Xpert MTB/RIF and GenoType MTBDRplus, represent promising test for TB diagnosis drug resistance detection.