title: Tuberculin skin test reversion following isoniazid preventive therapy reflects diversity of immune response to primary Mycobacterium tuberculosis infection.
abstract: BACKGROUND
  Healthy household contacts (HHC) of individuals with Tuberculosis (TB) with Tuberculin Skin Test (TST) conversions are considered to harbor latent Mycobacterium tuberculosis (Mtb), and at risk for TB. The immunologic, clinical, and public health implications of TST reversions that occur following Isoniazid preventive therapy (IPT) remain controversial.
  
  
  OBJECTIVE
  To measure frequency of TST reversion following IPT, and variation in interferon-gamma (IFN-γ) responses to Mtb, in healthy Ugandan TB HHC with primary Mtb infection evidenced by TST conversion.
  
  
  METHODS
  Prospective cohort study of healthy, HIV-uninfected, TST-negative TB HHC with TST conversions. Repeat TST was performed 12 months following conversion (3 months following completion of 9 month IPT course) to assess for stable conversion vs. reversion. Whole blood IFN-γ responses to Mtb antigen 85B (MtbA85B) and whole Mtb bacilli (wMtb) were measured in a subset (n = 27 and n = 42, respectively) at enrollment and TST conversion, prior to initiation of IPT.
  
  
  RESULTS
  Of 122 subjects, TST reversion was noted in 25 (20.5%). There were no significant differences in demographic, clinical, or exposure variables between reverters and stable converters. At conversion, reverters had significantly smaller TST compared to stable converters (13.7 mm vs 16.4 mm, respectively; p = 0.003). At enrollment, there were no significant differences in IFN-γ responses to MtbA85B or wMTB between groups. At conversion, stable converters demonstrated significant increases in IFN-γ responses to Ag85B and wMtb compared to enrollment (p = 0.001, p<0.001, respectively), while there were no significant changes among reverters.
  
  
  CONCLUSIONS
  TST reversion following IPT is common following primary Mtb infection and associated with unique patterns of Mtb-induced IFN-γ production. We have demonstrated that immune responses to primary Mtb infection are heterogeneous, and submit that prospective longitudinal studies of cell mediated immune responses to Mtb infection be prioritized to identify immune phenotypes protective against development of TB disease.
authors.affiliation: Tuberculosis Research Unit (TBRU), Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Denise F
authors.initials: DF
authors.lastname: Johnson
authors.affiliation: Tuberculosis Research Unit (TBRU), Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: LaShaunda L
authors.initials: LL
authors.lastname: Malone
authors.affiliation: Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda.
authors.forename: Sarah
authors.initials: S
authors.lastname: Zalwango
authors.affiliation: Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda.
authors.forename: Joy
authors.initials: J
authors.lastname: Mukisa Oketcho
authors.affiliation: Tuberculosis Research Unit (TBRU), Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Chervenak
authors.affiliation: Tuberculosis Research Unit (TBRU), Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Thiel
authors.affiliation: Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda; Department of Medicine, Makerere University College of Health Science, Kampala, Uganda.
authors.forename: Harriet
authors.initials: H
authors.lastname: Mayanja-Kizza
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Stein
authors.affiliation: Tuberculosis Research Unit (TBRU), Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: W Henry
authors.initials: WH
authors.lastname: Boom
authors.affiliation: Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Lancioni
mesh_terms: D000293:Adolescent; D000328:Adult; D000995:Antitubercular Agents / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007107:Immune System / Q000187:drug effects; D007371:Interferon-gamma / Q000378:metabolism; D007538:Isoniazid / Q000627:therapeutic use*; D055985:Latent Tuberculosis / Q000188:drug therapy / Q000517:prevention & control; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis; D010641:Phenotype; D011446:Prospective Studies; D014374:Tuberculin Test; D014376:Tuberculosis / Q000382:microbiology* / Q000517:prevention & control*; D014454:Uganda; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D007371:Interferon-gamma; D007538:Isoniazid