title: Biomarkers for discrimination between latent tuberculosis infection and active tuberculosis disease.
abstract: We aimed to determine whether combinations of multiplex cytokine responses could differentiate Mycobacterium tuberculosis (Mtb) infection states.
  
  
  
  Mtb-specific antigen-induced and unstimulated cytokines were measured by Luminex assay in supernatants of QuantiFERON®Gold In-Tube assay (QFT) in 48 active pulmonary TB patients (TB), 15 latent TB infection subjects (LTBI), and 13 healthy controls (HCs).
  
  
  
  Among the 29 cytokines, eight Mtb antigen-specific biomarkers (GM-CSF, IFN-γ, IL-1RA, IL-2, IL-3, IL-13, IP-10, and MIP-1β) in the Mtb-infected group were significantly different from those of the HCs. Five Mtb-specific biomarkers (EGF, GM-CSF, IL-5, IL-10, and VEGF), two unstimulated biomarkers (TNF-α[Nil]and VEGF[Nil]), and one Mtb-specific biomarker ratio (IL-2/IFN-γ) showed significant differences between active TB and LTBI. Three unstimulated biomarkers (IL-8[Nil], IL-13[Nil], and VEGF[Nil]) and 5 Mtb-specific biomarkers (IFN-γ, IL-2, IL-3, IP-10, and VEGF) were significantly different between active TB and non-active TB groups. Combinations of three cytokine biomarkers resulted in the accurate prediction of 92.1-93.7% of Mtb-infected cases and 92.3-100% of HCs, respectively. Moreover, combinations of five biomarkers accurately predicted 90.9-100% of active TB cases and 80-100% of LTBI subjects, respectively. In discriminating between active TB and non-active TB regardless of QFT results, combinations of six biomarkers predicted 79.2-95.8% of active TB cases and 67.9-89.3% of non-active TB subjects.
  
  
  
  Taken together, our data suggest that combinations of whole blood Mtb antigen-dependent cytokines could serve as biomarkers to determine TB disease states. Especially, VEGF is highlighted as a key biomarker for reflecting active TB, irrespective of stimulation.
authors.affiliation: Department of Laboratory Medicine, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea.
authors.forename: Eun-Jeong
authors.initials: EJ
authors.lastname: Won
authors.affiliation: Department of Laboratory Medicine, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea.
authors.forename: Jung-Ho
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea.
authors.forename: Young-Nan
authors.initials: YN
authors.lastname: Cho
authors.affiliation: Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea.
authors.forename: Hye-Mi
authors.initials: HM
authors.lastname: Jin
authors.affiliation: Heart Research Center, Chonnam National University Hospital, Gwangju, Republic of Korea.
authors.forename: Hae Jin
authors.initials: HJ
authors.lastname: Kee
authors.affiliation: Heart Research Center, Chonnam National University Hospital, Gwangju, Republic of Korea.
authors.forename: Yong-Wook
authors.initials: YW
authors.lastname: Park
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea. Electronic address: yskwon@jnu.ac.kr.
authors.forename: Yong-Soo
authors.initials: YS
authors.lastname: Kwon
authors.affiliation: Department of Laboratory Medicine, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea. Electronic address: sjkee@jnu.ac.kr.
authors.forename: Seung-Jung
authors.initials: SJ
authors.lastname: Kee
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000942:Antigens, Bacterial / Q000276:immunology; D015415:Biomarkers / Q000097:blood*; D016207:Cytokines / Q000097:blood* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D059425:Interferon-gamma Release Tests; D055985:Latent Tuberculosis / Q000097:blood / Q000175:diagnosis* / Q000382:microbiology; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology; D014376:Tuberculosis / Q000097:blood / Q000175:diagnosis* / Q000382:microbiology; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*; D055815:Young Adult
chemical_list: D000942:Antigens, Bacterial; D015415:Biomarkers; D016207:Cytokines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: Cytokines; Interferon-gamma release assay; Latent tuberculosis; Pulmonary tuberculosis