title: Robust Reconstitution of Tuberculosis-Specific Polyfunctional CD4+ T-Cell Responses and Rising Systemic Interleukin 6 in Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome.
abstract: BACKGROUND
  The immunopathogenesis of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) remains unclear. We determined the association between pathogen-specific T-cell responses and development of paradoxical TB-IRIS on antiretroviral therapy (ART).
  
  
  METHODS
  This study was nested within a prospective cohort study of HIV-infected patients with active pulmonary tuberculosis and baseline CD4 counts ≤125 cells/µL initiating ART. T-cell immune activation (CD38, HLA-DR, and PD-1 expression), phenotype, and polyfunctional pathogen-specific cellular immune responses prior to and 4 weeks after ART initiation were determined by flow cytometry. Patients with TB-IRIS were compared to non-IRIS controls using χ(2) and rank-sum tests and logistic regression.
  
  
  RESULTS
  TB-IRIS patients and controls had similar CD4 counts, levels of T-cell-associated immune activation, frequencies of T-cell memory subsets, and frequencies of interferon gamma (IFN-γ(+))/interleukin 2 (IL-2(+))/tumor necrosis factor alpha (TNF-α(+)) CD4(+) T-cells prior to ART initiation. After ART initiation, cellular immune activation and T-cell subsets also were similar in TB-IRIS patients and controls. In contrast, TB-IRIS patients had significantly greater early increases in the frequency of tuberculosis-specific polyfunctional IFN-γ(+)/IL-2(+)/TNF-α(+) CD4(+) T-cells on ART (P = .02); each quartile increase in the percentage of these cells was independently associated with a 2.8-fold increased risk of TB-IRIS (95% confidence interval, 1.1 to 7.5-fold). In a secondary analysis, patients with TB-IRIS had rapid, concomitant increases in tuberculosis-specific adaptive immune responses and interleukin 6 (IL-6) levels, whereas controls with similarly rapid increases in cellular immune function had IL-6 levels that tended to decrease on ART.
  
  
  CONCLUSIONS
  Rapid expansion of tuberculosis-specific polyfunctional CD4(+) T-cell responses, likely linked to increases in IL-6, is associated with development of paradoxical TB-IRIS.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.|Botswana-UPenn Partnership, Gaborone.
authors.forename: Shruthi
authors.initials: S
authors.lastname: Ravimohan
authors.affiliation: Botswana-UPenn Partnership, Gaborone.
authors.forename: Neo
authors.initials: N
authors.lastname: Tamuhla
authors.affiliation: Botswana-UPenn Partnership, Gaborone.
authors.forename: Kebatshabile
authors.initials: K
authors.lastname: Nfanyana
authors.affiliation: Botswana-UPenn Partnership, Gaborone.|Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania.|Children's Hospital of Philadelphia.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Steenhoff
authors.affiliation: Botswana-UPenn Partnership, Gaborone.
authors.forename: Rona
authors.initials: R
authors.lastname: Letlhogile
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
authors.forename: Ian
authors.initials: I
authors.lastname: Frank
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
authors.forename: Rob Roy
authors.initials: RR
authors.lastname: MacGregor
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.|Botswana-UPenn Partnership, Gaborone.|Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
authors.forename: Robert
authors.initials: R
authors.lastname: Gross
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.|Botswana-UPenn Partnership, Gaborone.
authors.forename: Drew
authors.initials: D
authors.lastname: Weissman
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.|Botswana-UPenn Partnership, Gaborone.|Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Bisson
mesh_terms: D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects; D001902:Botswana / Q000453:epidemiology; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D060085:Coinfection / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology / Q000821:virology; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy / Q000453:epidemiology / Q000276:immunology*; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000453:epidemiology / Q000276:immunology* / Q000401:mortality / Q000503:physiopathology*; D007111:Immunity, Cellular; D015850:Interleukin-6 / Q000097:blood*; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D011446:Prospective Studies; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000276:immunology*; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; C508600:IL6 protein, human; D015850:Interleukin-6
keywords: ART; HIV; cellular immune function; immune reconstitution inflammatory syndrome (IRIS); tuberculosis