title: Plasma interleukin-18 levels are a biomarker of innate immune responses that predict and characterize tuberculosis-associated immune reconstitution inflammatory syndrome.
abstract: BACKGROUND
  Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a substantial problem in HIV/TB coinfected patients commencing antiretroviral therapy (ART). The immunopathogenesis of TB-IRIS includes increased production of proinflammatory chemokines and cytokines, including interleukin-18, which is a signature cytokine of the nucleotide-binding domain and leucine-rich repeat pyrin containing protein-3 inflammasome. We compared plasma levels of interleukin-18 and other biomarkers of monocyte/macrophage activation in the prediction and characterization of TB-IRIS.
  
  
  METHODS
  Biomarkers were assayed pre-ART and during TB-IRIS, or equivalent time-point, in a case-control study of Malaysian HIV patients with paradoxical or unmasking TB-IRIS (n = 15), TB no IRIS (n = 14), and no TB or IRIS (n = 15). Findings for interleukin-18 were verified in another cohort of patients with paradoxical TB-IRIS (n = 26) and their controls (n = 22) from India.
  
  
  RESULTS
  Interleukin-18 was higher in TB-IRIS patients pre-ART and during the event in both Malaysian patients (P < 0.0001) and Indian patients (P < 0.01). CXCL10 was higher pre-ART (P < 0.001), mainly in paradoxical TB-IRIS patients, and during TB-IRIS (P < 0.001), whereas CXCL8 was only higher during TB-IRIS (P < 0.001). Soluble(s) CD14 was increased in all patients with HIV/TB coinfection pre-ART and during TB-IRIS or equivalent time-point, compared with patients without TB. In contrast, interferon-γ was lower before and during TB-IRIS. By receiver operating curve analysis, CXCL10, and/or interleukin-18 pre-ART were predictive of TB-IRIS.
  
  
  CONCLUSIONS
  Plasma interleukin-18 levels pre-ART are candidate biomarkers for predicting paradoxical and unmasking TB-IRIS and should be investigated for risk stratification and elucidation of disease pathogenesis.
authors.affiliation: aFaculty of Medicine, Centre of Excellence for Research in AIDS (CERiA), University of Malaya, Kuala Lumpur, Malaysia bNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA cFaculty of Medicine, Tropical Infectious Diseases Research and Education Centre (TIDREC), Department of Medical Microbiology dInfectious Disease Unit, Department of Medicine, University of Malaya Medical Centre, Kuala Lumpur, Malaysia eNational Institute for Research in Tuberculosis, Chennai, India fCentre for Biomedical Research, Macfarlane Burnet Institute for Medical Research and Public Health gInfectious Diseases Unit, The Alfred Hospital hDepartment of Infectious Diseases, Monash University, Melbourne iSchool of Pathology and Laboratory Medicine, University of Western Australia jDepartment of Clinical Immunology, Royal Perth Hospital and PathWest Laboratory Medicine, Perth, Western Australia, Australia.
authors.forename: Hong Yien
authors.initials: HY
authors.lastname: Tan
authors.forename: Yean Kong
authors.initials: YK
authors.lastname: Yong
authors.forename: Bruno B
authors.initials: BB
authors.lastname: Andrade
authors.forename: Esaki M
authors.initials: EM
authors.lastname: Shankar
authors.forename: Sasheela
authors.initials: S
authors.lastname: Ponnampalavanar
authors.forename: Sharifah F S
authors.initials: SF
authors.lastname: Omar
authors.forename: Gopalan
authors.initials: G
authors.lastname: Narendran
authors.forename: Adeeba
authors.initials: A
authors.lastname: Kamarulzaman
authors.forename: Soumya
authors.initials: S
authors.lastname: Swaminathan
authors.forename: Irini
authors.initials: I
authors.lastname: Sereti
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Crowe
authors.forename: Martyn A
authors.initials: MA
authors.lastname: French
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D000942:Antigens, Bacterial / Q000276:immunology; D000995:Antitubercular Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D018791:CD4 Lymphocyte Count; D060085:Coinfection; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000276:immunology* / Q000503:physiopathology; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000276:immunology* / Q000503:physiopathology; D007113:Immunity, Innate / Q000276:immunology*; D020382:Interleukin-18 / Q000097:blood / Q000276:immunology*; D008297:Male; D011446:Prospective Studies; D014376:Tuberculosis / Q000097:blood / Q000276:immunology* / Q000503:physiopathology
chemical_list: D019380:Anti-HIV Agents; D000942:Antigens, Bacterial; D000995:Antitubercular Agents; D015415:Biomarkers; D020382:Interleukin-18