title: Strong anti-Epstein Barr virus (EBV) or cytomegalovirus (CMV) cellular immune responses predict survival and a favourable response to anti-tuberculosis therapy.
abstract: BACKGROUND
  Intact immune responses to cytomegalovirus (CMV) and Epstein-Barr virus (EBV) represent a biologically and clinically relevant correlate of 'immunological fitness' in humans. However, there is a lack of knowledge concerning anti-EBV or anti-CMV responses in patients with pulmonary tuberculosis (TB), in whom aberrant immune responses may promote progression of clinical disease.
  
  
  METHODS
  Venous blood samples were obtained at the time of (sputum smear positive) pulmonary TB diagnosis. A whole blood assay was performed by exposing PBMCs (peripheral blood mononuclear cells) to a panel of infectious antigens, including CMV, EBV and mycobacterial proteins. Cell culture supernatants were collected after seven days and interferon gamma (IFN-γ) was measured using a sandwich ELISA. Patients received standard first line anti-tuberculosis rifampicin (R)/isoniazid (H)/ethambutol (E)/pyrazinamide (Z) for two months followed by RH for four months.
  
  
  RESULTS
  PBMCs from cured patients (after treatment completion) exhibited significantly stronger IFN-γ responses to CMV (p=0.035), EBV (p=0.006) or Mycobacterium tuberculosis ESAT-6 (p=0.043) at the time of diagnosis as compared to patients who succumbed to TB during treatment. IFN-γ responses to other viral (H5N1, HSV-1) as well as other mycobacterial (Ag85A, Rv2958c, Rv0447c) antigens were not found to be significantly different among patients who were cured or those who succumbed to TB.
  
  
  CONCLUSIONS
  Increased cellular immune responses to CMV and EBV antigens at the time of diagnosis of pulmonary tuberculosis are associated with increased survival after a standard six months anti-TB therapy. CVM and EBV antigens may represent "intrinsic markers for immune fitness" and guide improved TB therapies including host-directed therapies.
authors.affiliation: Division of Therapeutic Immunology (TIM), Department of Laboratory Medicine (LABMED), Karolinska Institutet, Stockholm and the Center for allogeneic stem cell transplantation (CAST), Karolinska University Hospital, Sweden; Department of Internal Medicine, Muhimbili University of Health and Allied Sciences (MUHAS), Dar es Salaam, Tanzania.
authors.forename: Tumaini
authors.initials: T
authors.lastname: Nagu
authors.affiliation: Department of Microbiology and Immunology, Muhimbili University of Health and Allied Sciences (MUHAS), Dar es Salaam, Tanzania.
authors.forename: Said
authors.initials: S
authors.lastname: Aboud
authors.affiliation: Division of Therapeutic Immunology (TIM), Department of Laboratory Medicine (LABMED), Karolinska Institutet, Stockholm and the Center for allogeneic stem cell transplantation (CAST), Karolinska University Hospital, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Rao
authors.affiliation: Department of Microbiology and Immunology, Muhimbili University of Health and Allied Sciences (MUHAS), Dar es Salaam, Tanzania.
authors.forename: Mecky
authors.initials: M
authors.lastname: Matee
authors.affiliation: Department of Microbiology and Immunology, Muhimbili University of Health and Allied Sciences (MUHAS), Dar es Salaam, Tanzania.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Axelsson
authors.affiliation: Department of Internal Medicine, Muhimbili University of Health and Allied Sciences (MUHAS), Dar es Salaam, Tanzania.
authors.forename: Davide
authors.initials: D
authors.lastname: Valentini
authors.affiliation: Department of Internal Medicine, Muhimbili University of Health and Allied Sciences (MUHAS), Dar es Salaam, Tanzania.
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Mugusi
authors.affiliation: Division of Infection and Immunity, University College London, and NIHR Biomedical Research Centre, UCL Hospitals NHS Foundation Trust, London, United Kingdom.
authors.forename: Alimuddin
authors.initials: A
authors.lastname: Zumla
authors.affiliation: Division of Therapeutic Immunology (TIM), Department of Laboratory Medicine (LABMED), Karolinska Institutet, Stockholm and the Center for allogeneic stem cell transplantation (CAST), Karolinska University Hospital, Sweden; Centre for Allogeneic Stem cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden. Electronic address: markus.maeurer@ki.se.
authors.forename: Markus
authors.initials: M
authors.lastname: Maeurer
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003587:Cytomegalovirus / Q000276:immunology*; D005260:Female; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D008297:Male; D011237:Predictive Value of Tests; D016896:Treatment Outcome; D032581:Tuberculosis Vaccines / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000276:immunology* / Q000401:mortality
chemical_list: D000995:Antitubercular Agents; D032581:Tuberculosis Vaccines
keywords: CMV; EBV; IFN-γ; TB therapy,; cellular immune response; pulmonary tuberculosis; survival