TABLE 1.

Biomarkers for diagnosis, prognosis, and monitoring of MTB infection.

	Biomarker	Specimen					Application					Remark
		Sputum	Body fluids	CSF	Blood/serum/plasma	PBMC	Mtb diagnosis	Distinguish active TB vs. LTBI	Monitoring	Predict relapse/worsen/progress	Predict treatment success
Microbiology technique	AFB staining	∙	∙	∙	∙		∙		∙			– Rapid, convenient and inexpensive test
												– Non-specific, must accompanied with confirmation tests
												– Limited sensitivity; required at least 5000 AFB/mL to be detected
												– High false negative rate
	Mtb culture	∙	∙	∙	∙		∙		∙			– Long turnaround time (3–8 weeks)
												– Required biosafety level three facilities to handle Mtb culture
Detection of Mtb components	Mtb DNA detection (GeneEpert)	∙	∙	∙	∙		∙			∙		– Rapid, diagnosis, and detection of drug resistant Mtb
												– Low sensitivity (49–72%)
												– Patient positive with Mtb in blood assoc. with increased risk of death
	Mtb antigens ∙ LAM		∙						∙	∙		– Low sensitivity (13–93%)
												– Use to monitor anti-TB response in TB-HIV
												– co-infected patients
												– Predict TB-IRIS and death among TB-HIV co-infected patients
	Mtb antigens ∙ Ag 85 complex, ESAT-6, CFP-10, MPT64	∙	∙	∙	∙							– Sensitivity is in consistent Poor specificity
	Digital PCR (dPCR)				∙		∙					– Supreme sensitivity then conventional qPCR
												– Twofold higher sensitivity than GeneXpert in detecting MTB among probable/possible TB meningitis
												– The study uses CSF, but can be apply for sputum, serum/plasma and other body fluid
Host antibodies responses against ex-vivo stimulation of Mtb Ags	PPD, Ag60, ESAT-6, CFP-10	∙			∙							– Poor sensitivity (14–85%); poor specificity (53–98%)
												– Antibody response usually very low among children
	RV0310c-E				∙		∙					– Better sensitivity than ESAT-6 and CFP-10
	RV1255c-E
	P12037				∙		∙					– Sensitivity = 92%, specificity = 91%
	PPE17				∙		∙	∙	∙			– More antigenic antigen than ESAt-6 and CFP-10
	MDP-1
	RV2031c, RV1408, RV2421c				∙		∙	∙				– IgG against these three Ags were initial identified by screening done by proteomics
Host cytokines responses against ex-vivo stimulation of MTB Ags	Tuberculin skin test (TST)	–	–	–	–	–	∙	∙	∙			– Poor sensitivity among HIV/immunocompromised patients
	Ag: ESAT-6, CFP-10 IFN-γ (IGRA)				∙	∙	∙			∙	∙	– T-SPOT sensitivity (91.2%); QuantiFERON sensitivity (80.2%)
												– More specific than TST
												– Less affected by HIV-status compared to TST
												– Predict TB-reactivation within 2 years
												– Associated with complete clinical and microbiological recovery
	Ag: ESAT-6, CFP-10 IP-10				∙		∙	∙				– High IP-10 in unstimulated tube associated with active TB
												– Less affected by HIV status
	Ag: ESAT-6, CFP-10 sCD14, MD-2, LPS				∙		∙	∙			∙	– Distinguish between active-TB and LTBI
												– Levels correlated with treatment success
	Ag: ESAT-6, CFP-10 IL-8, MIP-1a, sIL-2Ra, VEGF, MCP-3				∙		∙	∙
	Ag: ESAT-6, CFP-10 IL-6, MCP-1, VEGF, HO-1, MMP, IL-11R antagonist, 2-antiplasmin				∙						∙
Host cytokines responses against ex-vivo stimulation of MTB Ags	Ag: ESAT-6, CFP-10 ratio of IL-2/IFN-γ				∙		∙	∙
	Ag: ESAT-6, CFP-10 eotaxin, CCL22, MCP-1				∙		∙	∙				– When used in combination, the sensitivity = 87.8% and specificity = 91.8%
	Ag: DosR, RV2029c, Rpf, RV2389c IFN-γ (IGRA)				∙	∙	∙	∙				– Both DosR and Rpf are antigen expressed during latent infection
												– When used in combination, the sensitivity = 90% and specificity = 85%
Host cellular immune responses against ex-vivo stimulation of Mtb antigens	CD4 + CD69 + IFN-γ+					∙	∙	∙				– Associate with early or recent Tb-infection
	CD4 + IFN-γ + IL-2 + TEM					∙	∙	∙				– Associated with LTBI
	CD4 + IL-2 + TCM					∙	∙	∙				– Associated with LTBI
	CD4 + IFN-γ + TEMRA					∙	∙	∙			∙	– Associated with active TB-infection
												– Shift of functional signature from CD4 + IFN-γ + TEMRA to CD4 + IFN-γ + IL-2 + TEM after completion of ATT indicate successful treatment
	CD4 + IFN-γ + IL-2 + TNF-α+					∙	∙	∙			∙	– Associated with active TB-infection
	CD4 + IFN-γ + IL-2+					∙	∙	∙			∙	– Associated with active LTBI
	CD4 + IFN-γ+					∙	∙	∙			∙	– Associated with active LTBI
												– Shift of functional signature from CD4 + IFN-γ + TNF-α + to CD4 + IFN-γ + IL-2 + or CD4 + IFN-γ + after completion of ATT indicate successful treatment
	TEM TCM					∙				∙	∙	– High TEM at sixth months of ATT assoc. with TB reactivation
												– High TCM at sixth months of ATT assoc. with complete clearance of TB
	CD4 + CD27+					∙	∙	∙				– Differentiate between active TB and LTBI
												– High CD4 + CD27 + associated with active TB
												– Intermediate CD4 + CD27+ associated with LTBI
	CD137 + T-cells				∙	∙						– Is a member of TNF receptor superfamily
												Associated with active TB
	IL-10 + Th17				∙	∙		∙				– Associated with LTBI, when stimulated with DosR
	IFN-γ + Th17				∙	∙		∙				– Associated with active TB, when stimulated with DosR
	%BDCA3 + mDC				∙	∙		∙				– Reduction in% indicated active TB infection
	%CD123 + pDC
	MFI BDCA3 + mDC				∙	∙		∙				– Increase activation markers in these subsets indicated LTBI
	MFI CD123 + pDC
	CD38, HLA-DR								∙	∙	∙	– Used for monitoring of time to culture conversion after initiation of anti-TB therapy
												– Slope of reduction in CD38 and HLA-DR correlated with time to culture conversion
	Treg								∙	∙	∙	– Low% of Treg found among rapid responder
												– Percentage of Treg inversely correlated with time to culture conversion
Genomics, transcriptomic, proteomics, and metabolomics	∙ Neutrophil derived IFN-γ, IFN-α and β					∙	∙	∙				– Further validations required
	∙ FcγR1B					∙	∙	∙				– Further validations required
	∙ Lacto transferrin CD64, RIN3					∙	∙	∙				– Further validations required
	circRNA _103017, _059914, _101128, _062400				∙	∙		∙				– Covalently closed circular RNA, highly resistant to RNase, hence presence in abundance in cytoplasm
												– Increase in these three circRNAs is associated with LTBI
												– Decreased in this circRNA is associated with active TB infection
	host miRNA				∙		∙	∙				– Increase in these miRNA is associated with active TB infection
	_hsa-miR-146a-5p
	_hsa-miR-125b-5p
	MTB miRNA
	_MTB-miR5				∙		∙	∙
	Host miRNA				∙		∙	∙				– Elevation of these miRNA were associated with LTBI
	_hsa-let-7e-5p
	_hsa-let-7d-5p
	_hsa-miR-450a-5p
	_hsa-miR-140-5p
	Host miRNA				∙		∙	∙				– Elevation of these miRNA were
	_hsa-miR-1246
	_ hsa-miR-2110											– associated with active TB infection
	_ hsa-miR-370-3p
	_ hsa-miR-28-3p
	_ hsa-miR-193b-5p
	Host proteomics				∙					∙	∙	– Elevation of these plasma markers were associated with severe TB infection
	ORM2, IL-36α,
	S1000-A9, SOD
	Host metabolomics ∙ Cortisol, tryptophan, glutathione, tRNA acylation				∙					∙		– Predict progression from LTBI to active TB (applicable to host hold contact of TB infected individual)
	Host genomics ∙ SNP of SP110 gene (rs9061)					∙				∙		– SP100 gene encoding for IFN induced nuclear protein
												– Individual bearing this SNP was associated lower plasma level of TNF and increase susceptibility to LTBI