title: Predictive value of serum bradykinin and desArg9-bradykinin levels for chemotherapeutic responses in active tuberculosis patients: A retrospective case series.
abstract: There is an urgent need for methods that can rapidly and accurately assess therapeutic responses in patients with active tuberculosis (TB) in order to predict treatment outcomes. Exposure to bacterial pathogens can rapidly activate the plasma contact system, triggering the release of bradykinin (BK) and its metabolite desArg9-bradykinin (DABK) to induce inflammation and innate immune responses. We hypothesized that serum BK and DABK levels might act as sensitive immune response signatures for changes in Mycobacterium tuberculosis (Mtb) burden, and therefore examined how serum levels of these markers corresponded with anti-TB therapy in a small cohort of active TB cases.
  
  
  
  Nanotrap Mass-Spectrometry (MS) was used to analyze serial blood specimens from 13 HIV-negative adults with microbiologically confirmed active TB who were treated with first-line anti-TB chemotherapy. MS signal for BK (m/z 1060.5) and DABK (m/z 904.5) serum peptides were evaluated at multiple time-points (before, during, and after treatment) to evaluate how BK and DABK levels corresponded with disease status.
  
  
  
  Serum BK levels declined from pretreatment baseline levels during the early stage anti-TB therapy (induction phase) and tended to remain below baseline levels during extended treatment (consolidation phase) and after therapy completion. BK levels were consistent with induction phase sputum culture conversions indicative of decreased Mtb burden reflecting good treatment responses. Serum DABK levels tended to increase during the induction phase and decrease at consolidation and post-therapy time points, which may indicate a shift from active disease to chronic inflammation to a disease free state. Elevated BK and DABK levels after treatment completion in one patient may be related to the subsequent recurrent TB disease.
  
  
  
  Our pilot data suggests that changes in the circulating BK and DABK levels in adult TB patients can be used as potential surrogate markers of the host response both early and late in anti-TB treatment for both pulmonary and extrapulmonary TB patients. We will further exploit these host-response signatures in the future as biomarkers in combination with other clinical and microbiologic tools which may improve treatment efficacy and facilitate the development of host-directed therapy.
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, 77030, USA; Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, Wenzhou, 325035, PR China.
authors.forename: Xu
authors.initials: X
authors.lastname: Qian
authors.affiliation: HMRI Molecular Tuberculosis Laboratory, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, TX, 77030, USA.
authors.forename: Duc T M
authors.initials: DTM
authors.lastname: Nguyen
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, 77030, USA.
authors.forename: Yaojun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, Wenzhou, 325035, PR China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Lyu
authors.affiliation: HMRI Molecular Tuberculosis Laboratory, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, TX, 77030, USA. Electronic address: eagraviss@houstonmethodist.org.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Graviss
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, 77030, USA; Weill Cornell Medical College of Cornel University, New York City, NY, 10065, USA. Electronic address: yhu@houstonmethodist.org.
authors.forename: Tony Y
authors.initials: TY
authors.lastname: Hu
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000097:blood; D015536:Down-Regulation; D006801:Humans; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000302:isolation & purification; D050997:Nanomedicine / Q000379:methods; D010865:Pilot Projects; D011237:Predictive Value of Tests; D012008:Recurrence; D012074:Remission Induction; D012189:Retrospective Studies; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013183:Sputum / Q000382:microbiology; D013997:Time Factors; D016896:Treatment Outcome; D014376:Tuberculosis / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D015415:Biomarkers; C024626:bradykinin, des-Arg(9)-; D001920:Bradykinin
keywords: Antibiotics; Bradykinin; Outcome; Recurrence; Treatment response; Tuberculosis