Immunological Aspects of Diagnosis and Management of Childhood Tuberculosis

Figures & data

Table 1 Factors Pointing Toward Personalized Diagnosis

Standard Diagnosis of Pulmonary TB in Children					Ref.
	Clinical Features	Microbiological Tests Sensitivity	DNA Tests (Xpert MTB/RIF) Sensitivity	IFN-g Release Assays (QFT-Gold Sensitivity)
<3 years old	Asymptomatic or few symptoms. “Silent” infection. Ghon focus, lymph node disease.	Less of 40%, even in samples derived from gastric aspirates and induced sputum.	Children < 1 year is 75% in gastric aspirates	Only 54% are positively in part by immature immune response.	^Citation2,Citation13, ^Citation15^–^Citation18, ^Citation25,Citation62^–^Citation64
<10 years old	Ghon focus, lymph node disease, bronchial disease.	Sputum smears: about 20%. Cultures: < 40%.	>1–10 years is 100% in gastric aspirates and induced sputum.	About 11–40%.
Older children and adolescents	Primary form or pulmonary disease. Classic bacillary impregnation syndrome, cavitation and hemoptysis.	Smear sputum is usually positive	11-<15, is 89% in sputum.	11–40%. IGRAs may be used to help support the diagnosis of active TB.
Conditions that modify TB disease and standard diagnosis tools
Age	Children under three years are at the highest risk for rapid progression to active TB, they have a paucibacillary condition, non sputum.				^Citation2,Citation3,Citation25,Citation27,Citation28,Citation30,Citation32,Citation39^–^Citation41, ^Citation48^–^Citation50, ^Citation56^–^Citation63.
Nutrition	Malnourished children have high TB burden. Malnutrition is associated with lower levels of IFN-g in response to TB antigens.
BCG vaccination	Unvaccinated children have higher probability of developing active TB and more severe clinical forms of TB, meningitis, and miliary TB.
Immune status	The disease expression is directly linked to immune function. Neonates and infants have lower capacity of APCs to present antigens to T cells. M. tuberculosis-ESAT-6- specific CD4+ T cells number is lower in younger children (0–3 years old). Children < 5 years old do not produce IFN-g by CD8+ T cells in response to ESAT-6 and CFP-10.
Coinfections	Fungal coinfections are frequent in primary immunodeficiency diseases that cause T cell disorders and IL-17 overexpression. Coinfections with non-tuberculous mycobacteria affect 6% of children and may inhibit BCG vaccine effectiveness. Children < 15 years with HIV infection at higher risk of TB infection and active TB development. Human cytomegalovirus coinfection increases risk factors for TB infants.
Genetic immunodeficiencies	The Mendelian susceptibility to mycobacterial disease induces high susceptibility to infections. NEMO and five autosomal genes: IFNGR (1 and 2), STAT1, IL12B, and IL12RB1, are involved in the axes of IL‐12/IL‐23‐dependent and IFN-g‐mediated immunity.
New immunological tools for diagnosis of TB
RNA biomarkers	10-transcript signature that distinguishes TB in children has 97% of sensitivity. In children < 15 years, a 51-transcript signature of TB risk has 82% of sensitivity.				^Citation93,Citation94, ^Citation96^–^Citation99
Immunophenotype	TAM-TB assay has a sensitivity of 83% and a specificity of 97%. MAIT cells are lower in children with active TB.
MicroRNAs	14 different miRNAs are down-regulated while miR-29 is up-regulated in children with TB.
Hints for TB personalized diagnosis
Individual features of disease	Age, metabolic or nutritional conditions, BCG vaccination, drug-sensitivity, and coinfections could define the initial therapeutic regimens based on immunological evidence and support the use of personalized medicine.				104, ^Citation120^–^Citation123, 127–^Citation131
Discrimination of genetic conditions	Immunodeficiencies could be suspected within the clinical evaluation after BCG vaccination or environmental mycobacteria infections, as well as recurrent or prolonged infections that do not respond to adequate antibiotic therapy.
Status of the individual immune response	Evaluation of TLRs, NLRs, IL‐12/IL‐23 axes, or redox status, can be used for the identification of immunodeficiencies and immune markers response during infection, or to propose selected immunoactivators.

Note: Ghon focus: consisting of a granuloma, typically in the middle or lower zones of the lung.

Abbreviations: APC, antigen-presenting cells; TLR, Toll-like receptors; NLR, nucleotide-binding and oligomerization domain (NOD)-like receptors; NEMO, NF-κB essential modulator; IGRAs, IFN-γ release assays; MAIT, mucose-associated invariant T cells; TAM-TB, T-cell activation marker assay.

Figure 1 Multifactorial external and internal stimuli influence the immunological signatures. Malnutrition, BCG vaccination status, immune system maturation (associated with age), genetic susceptibility (as Mendelian susceptibility to mycobacterial disease), and coinfection induce a specific immune signature and determine the fate of TB.

Figure 2 Current tools to diagnose TB in children. The traditionally denominated golden standards microbiological culture and sputum smear microscopy set the diagnosis in adults, but children are challenging to prove positive for either of them. Currently, diagnosis in children should include one or more of the more sophisticated techniques.

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