title: Lymphocyte proliferation to mycobacterial antigens is detectable across a spectrum of HIV-associated tuberculosis.
abstract: BACKGROUND
  Identifying novel TB diagnostics is a major public health priority. We explored the diagnostic characteristics of antimycobacterial lymphocyte proliferation assays (LPA) in HIV-infected subjects with latent or active TB.
  
  
  METHODS
  HIV-infected subjects with bacille Calmette Guérin (BCG) scars and CD4 counts > or = 200 cells/mm(3) entering a TB booster vaccine trial in Tanzania had baseline in vivo and in vitro immune tests performed: tuberculin skin tests (TST), LPA and five day assays of interferon gamma (IFN-gamma) release. Assay antigens were early secreted antigenic target 6 (ESAT-6), antigen 85 (Ag85), and Mycobacterium tuberculosis whole cell lysate (WCL). Subjects were screened for active TB at enrollment by history, exam, sputum smear and culture. We compared antimycobacterial immune responses between subjects with and without latent or active TB at enrollment.
  
  
  RESULTS
  Among 1885 subjects screened, 635 had latent TB and 13 had active TB. Subjects with latent TB were more likely than subjects without TB to have LPA responses to ESAT-6 (13.2% vs. 5.5%, P < 0.0001), Ag85 (18.7% vs. 3.1%, P < 0.0001), and WCL (45.7% vs. 17.1%, P < 0.0001). Subjects with active TB also were more likely than those without active TB to have detectable LPA responses to ESAT-6 (38.5% vs. 8.1%, P = 0.0001), Ag85 (46.2% vs. 8.5%, P < 0.0001), and WCL (61.5% vs. 27.0%, P = 0.0053). In subjects with a positive TST, LPA responses to ESAT-6, Ag85 and WCL were more common during active TB (p < 0.0001 for all tests). In diagnosing active TB, in vivo and in vitro tests of mycobacterial immune responses had sensitivity and specificity as follows: TST 84.6% and 65.5%, ESAT-6 LPA 38.5% and 92.0%, Ag85 LPA 46.2% and 91.5%, and WCL LPA 61.5% and 73.0%. Detectable LPA responses were more common in patients with higher CD4 counts, and higher HIV viral loads.
  
  
  CONCLUSIONS
  Lymphoproliferative responses to mycobacteria are detectable during HIV-associated active TB, and are less sensitive but more specific than TST.
  
  
  BACKGROUND
  ClinicalTrials.gov Identifier NCT00052195.
authors.affiliation: Dartmouth Medical School, Lebanon, NH, USA. Timothy.Lahey@Dartmouth.edu
authors.forename: Timothy
authors.initials: T
authors.lastname: Lahey
authors.forename: Mecky
authors.initials: M
authors.lastname: Matee
authors.forename: Lillian
authors.initials: L
authors.lastname: Mtei
authors.forename: Muhammad
authors.initials: M
authors.lastname: Bakari
authors.forename: Kisali
authors.initials: K
authors.lastname: Pallangyo
authors.forename: C Fordham
authors.initials: CF
authors.lastname: von Reyn
mesh_terms: D000328:Adult; D000942:Antigens, Bacterial / Q000276:immunology*; D001500:BCG Vaccine / Q000008:administration & dosage / Q000276:immunology; D018791:CD4 Lymphocyte Count; D049109:Cell Proliferation; D005260:Female; D015658:HIV Infections / Q000382:microbiology*; D006801:Humans; D007117:Immunization, Secondary; D007371:Interferon-gamma / Q000032:analysis; D016015:Logistic Models; D008213:Lymphocyte Activation; D008297:Male; D015999:Multivariate Analysis; D013636:Tanzania; D014374:Tuberculin Test; D014376:Tuberculosis / Q000175:diagnosis* / Q000276:immunology*; D019562:Viral Load
chemical_list: D000942:Antigens, Bacterial; D001500:BCG Vaccine; D007371:Interferon-gamma