Tuberculosis

Tuberculosis (or TB) is caused by a bacterium called Mycobacterium tuberculosis. Every year, there are more than ten million new cases of TB globally and about two million people die from the disease, with about one-third of deaths due to drug resistance. Remarkably, 75% of TB cases occur in developing countries. In Viet Nam, TB is one of the top ten causes of death and the most common fatal infectious disease with an increasing number of drug resistant cases every year. There are many challenges to controlling TB, especially in resource limited countries.

The BCG vaccine can reduce severe TB in young children but is not very effective in adults. TB treatment commonly requires at least four different drugs to be taken daily for at least six months, or longer in patients with drug resistant or complicated TB. About 40 percent of TB cases are missed, mis-diagnosed and untreated. This can result in death or prolonged illness with increased disease transmission or development of drug resistance if wrongly treated. There are a lot of efforts to strengthen TB control, develop new drugs and vaccines and improve diagnostic tools and treatment for TB.

The objectives of the TB group are to improve TB diagnosis and treatment by carrying out clinical trials of new diagnostic tests and therapeutic approaches. We also aim to understand more about how genetic variations in both host and pathogen influence disease presentations and outcomes.

Our major research interests are:

Improving Treatment: TB meningitis (TBM) is the most severe form of TB causing death or neurological disability in half of all cases. To improve treatment outcomes, we have run clinical trials of modified anti-tuberculosis regimens and using adjunctive anti-inflammatory drugs. Patients’ LTA4H genotypes have been found regulate inflammation and predict survival. Ongoing studies in meningeal and pulmonary TB have the potential to establish therapies directed by host genotype.

Host Genetics in Susceptibility and Treatment Response: Host immunity plays an important role in bacterial control and inflammatory response, which then lead to different outcomes. We aim to link human genotype and immunological phenotype before and during TB treatment and thus improve outcomes. Regarding host susceptibility, we focus on genes involved in M. tuberculosis recognition and in regulating the immune response. We are also conducting RNA-Seq on clinical samples to reveal the pathogenesis of different forms of TB.

Transmission, Resistance and Tolerance: Modern Beijing strains of M. tuberculosis have increased significantly in Vietnam recently and shown greater transferrability and high virulence in our studies. We are using geographic and phylogenetic analysis of clinical isolates, together with cellular biology, to understand disease transmission and mechanisms of drug resistance and tolerance. We are also developing methods for rapid diagnosis of drug resistance using whole genome sequencing directly in clinical samples.

Our current active studies:

  1. Adjunctive corticosteroids for TBM in HIV-infected adults in Vietnam and Indonesia
  2. Leukotriene A4 hydrolase stratified trial of adjunctive corticosteroids for HIV-uninfected adults with TBM in Vietnam
  3. Shortened intensive anti-TB and anti-inflammatory (aspirin) for children with TBM in Uganda, Vietnam, Zambia, Zimbabwe
  4. Prospective randomised evaluation of the diagnostic performance of standard 1st generation GeneXpert MTB/RIF against GeneXpert MTB/RIF Ultra in TBM
  5. Prospective observational study of the host and bacterial determinants of outcome from multi-drug resistant pulmonary TB
  6. Retrospective, multi-drug resistant TB in Ho chi Minh City in the last 5 years
  7. Linking genotype and (immune) phenotype in TBM & multi-drug resistant TB using RNAseq
  8. T cell exhaustion in TB infection using RNAseq
  9. Geographic and phylogenetic analysis to understand how does TB transmit in a city
  10. How do patients get multi-drug resistant TB?
  11. tuberculosis antibiotic tolerance of clinical strains
  12. Early diagnosis of drug resistant TB by whole genome sequencing of clinical samples
  13. Genetic prediction of drug resistance by WGS: 100,000 strains (CRyPTIC project)
  14. Influence of host and bacterial genetics on macrophage function and TB outcomes

Research Locations

The OUCRU TB research group is located in the Hospital for Tropical Diseases, HCMC, Vietnam. We have built strong and long-standing collaborations with the Hospital for Tropical Diseases and Pham Ngoc Thach Hospital in HCMC and the National Lung Hospital in Hanoi to conduct clinical trials. We have also established connections with District TB Units in HCMC to study TB in the community. We are working closely with the Unit in Indonesia to and collaborating in the current trial. We are creating a TB research network in South East Asia (Vietnam, Thailand, Nepal, and Myanmar) to study pulmonary TB.

Researchers and PhD students working TB

  • Nguyễn Thụy Thương Thương, TB Group Head, Wellcome Trust Research Fellow
    Research interests: immunological pathogenesis, omics in TB susceptibility, treatment responsiveness and outcomes, host-pathogen interactions in TB
  • Guy Thwaites, OUCRU Director  
    Research interests: diagnosis and treatment of TBM, pathophysiology
  • Vijay Srinivasan, Postdoctoral Scientist
    Research interests: bacterial phenotypic and genotypic variation
  • Đào Nguyễn Vĩnh, Postdoctoral Scientist
    Research interests: mathematical modeling of TB transmission and resistance, omics in TB outcomes
  • Trịnh Thị Bích Trâm, Postdoctoral Scientist
    Research interests: host genetics and anti-microbial activity of macrophages in TB dissemination
  • Joseph Donovan, Clinical Research Physician, PhD student
    Research interests: diagnosis and treatment of TBM
  • Le Hong Van, Clinical Research Physician, PhD student
    Research interests: host determinants of treatment outcomes in multi-drug resistant pulmonary TB
  • Đỗ Đặng Anh Thư, Senior Research Assistant
    Research interests: clinical TB diagnosis, strain isolation, drug sensitivity testing
  • Vũ Thị Ngọc Hà, Senior Research Assistant
    Research interests: host and pathogen genotyping, bacterial whole genome sequencing, inflammatory response
  • Hoàng Ngọc Nhung, Senior Research Assistant
    Research interests: host-Mtb interaction using macrophage model, drug sensitivity phenotyping
  • Nguyễn Lê Hoài Bảo, Technician
  • Trần Dinh Dinh, Research Assistant
  • Vũ Thị Mộng Dung, Research Assistant
  • Hoàng Thanh Hải, Research Assistant
  • Nguyễn Thị Hạnh, Research Coordinator
  • Nguyễn Thị Thu Hiệp, Study Doctor
  • Phùng Võ Khắc Nguyên, Study Doctor
  • Phan Triệu Phú, Research Coordinator
  • Trần Phú Quang, Technician
  • Võ Thanh Sơn, Research Coordinator
  • Lê Phạm Tiến Triều, Technician

Key achievements/Outcomes

  • Improving treatment outcomes from TBM: Dexamethasone (now endorsed by WHO for TBM treatment) saves more lives (Thwaites et al NEJM 2004); timing of ARVs does not influence survival (Torok at al CID 2011); intensified TB therapy improves survival in INH-R TBM (Heemskerk et al NEJM 2016, Heemskerk et al CID 2017).
  • Improving diagnostic methods in TBM: We defined the use of GeneXpert MTB/RIF in diagnosis of TBM (Nhu at al JCM 2014) and pediatric TB (Giang et al BMC 2015). The largest prognostic study to date of mortality in TBM with 1699 cases (Thao et al CID 2017) identified common predictors for increased mortality.
  • Defining TB susceptibility and pathogenesis: Human Leukotriene A4 Hydrolase (LTA4H) genotype was found to determine TBM susceptibility and predict the effectiveness of adjuctive dexamethasone (Tobin et al Cell 2010 and 2012, Thuong et al JID 2017). Two large multi-centre clinical trials to personalized TBM treatment are underway (Donovan et al Wellcome Open Res 2018).
  • Defining TB drug resistance mechanisms and transmission: Associations between cell size and structure and drug resistance have been shown (Vijay et al Frontiers in Microbiology 2017 and 2018), whilst the spread of the Beijing lineage and positive selection of the EsxW Beijing variant in Vietnam have also been demonstrated (Holt et al Nature 2018).

Grants and Awards

  • Wellcome Trust Clinical Research Career Development Fellowship. How do people get multi-drug resistant tuberculosis? The Wellcome Trust, UK
  • Research Grant, Joint Funded Initiatives Full. Short enhanced anti-tuberculosis and anti-thrombosis treatment for children with tuberculous meningitis. The Medical Research Council (MRC), UK
  • Wellcome Trust Intermediate Fellowship. Linking human genotype and immunological phenotype to understand pathogenesis and improve treatment in tuberculosis. The Wellcome Trust, UK
  • Longitude Prize Discovery Awards, Nanopore sequencing of M. tuberculosis, Longitude Prize, UK
  • Wellcome Trust Investigator Award. Molecular characterisation of antibiotic tolerance in Mycobacterium tuberculosis. The Wellcome Trust, UK
  • Wellcome Trust Investigator Award. Personalised adjunctive anti-inflammatory therapy to reduce deaths from tuberculosis. The Wellcome Trust, UK
  • Wellcome Trust/ Newton Fund-MRC Collaborative Award, Comprehensive Resistance Prediction for Tuberculosis: an International Consortium (CRyPTIC). The Wellcome Trust and MRC, UK

Top 15 Publications

  1. Tram TTB, Nhung HN, Vijay S, Hai HT, Thu DDA, Ha VTN, Dinh TD, Ashton PM, Hanh NT, Phu NH, Thwaites GE, Thuong NTT. Virulence of Mycobacterium tuberculosis Clinical Isolates Is Associated with Sputum Pre-treatment Bacterial Load, Lineage, Survival in Macrophages, and Cytokine Response. Front Cell Infect Microbiol. 2018 Nov 27. PMID: 30538956.
  2. CRyPTIC Consortium and the 100,000 Genomes Project. Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing. N Engl J Med. 2018 Oct 11. PMID: 30280646
  3. Holt KE, McAdam P, Thai PVK, Thuong NTT, Ha DTM, Lan NN, Lan NH, Nhu NTQ, Hai HT, Ha VTN, Thwaites G, Edwards DJ, Nath AP, Pham K, Ascher DB, Farrar J, Khor CC, Teo YY, Inouye M, Caws M, Dunstan SJ; Frequent transmission of the Mycobacterium tuberculosis Beijing lineage and positive selection for the EsxW Beijing variant in Vietnam. Nat Genet; 2018 Jun. PMID: 29785015
  4. Donovan J, Phu NH, Thao LTP, Lan NH, Mai NTH, Trang NTM, Hiep NTT, Nhu TB, Hanh BTB, Mai VTP, Bang ND, Giang DC, Ha DTM, Day J, Thuong NT, Vien NN, Geskus RB, Hien TT, Kestelyn E, Wolbers M, Chau NVV, Thwaites GE. Adjunctive dexamethasone for the treatment of HIV-uninfected adults with tuberculous meningitis stratified by Leukotriene A4 hydrolase genotype (LAST ACT): Study protocol for a randomised double blind placebo controlled non-inferiority trial. Wellcome Open Res. 2018 Mar 20. PMID: 30363837
  5. Mai NT, Dobbs N, Phu NH, Colas RA, Thao LT, Thuong NT, Nghia HD, Hanh NH, Hang NT, Heemskerk AD, Day JN, Ly L, Thu DD, Merson L, Kestelyn E, Wolbers M, Geskus R, Summers D, Chau NV, Dalli J, Thwaites GE. A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults. Elife. 2018 Feb 27. PMID: 29482717
  6. Thai PVK, Ha DTM, Hanh NT, Day J, Dunstan S, Nhu NTQ, Kiet VS, Lan NH, Dung NH, Lan NTN, Thuong NT, Lan NN, Lieu PTT, Hong NT, Diep DC, Thanh NTK, Hoi NV, Nghia NV, Dai TN, Minh HQ, Thom NV, Farrar J, Caws M. Bacterial risk factors for treatment failure and relapse among patients with isoniazid resistant tuberculosis. BMC Infect Dis. 2018 Mar 6; 18(1):112. doi: 10.1186/s12879-018-3033-9. PMID: 29510687
  7. Thao LTP, Heemskerk AD, Geskus RB, Mai NTH, Ha DTM, Chau TTH, Phu NH, Chau NVV, Caws M, Lan NH, Thu DDA, Thuong NTT, Day J, Farrar JJ, Torok ME, Bang ND, Thwaites GE, Wolbers M. Prognostic Models for 9-Month Mortality in Tuberculous Meningitis. Clinical Infectious Diseases; 2018 Feb 1. PMID: 29029055.
  8. Vijay S, Dao N Vinh, Hoang T Hai, Vu TN Ha, Vu TM Dung, Tran D Dinh, Hoang N Nhung, Trinh TB Tram, Bree Aldridge, Thwaites GE, NTT Thuong. Influence of stress and antibiotic resistance on cell length distribution in Mycobacterium tuberculosis clinical Isolates. Frontiers in Microbiology; 21 November 2017. PMID: 29209302
  9. NTT Thuong, D Heemskerk, TTB Tram, LTP Thao, L Ramakrishnan, VTN Ha, ND Bang, TTH Chau, NH Lan, M Caws, Dunstan SJ, Chau NVV, Wolbers M, Mai NTH, Thwaites GE. Leukotriene A4 hydrolase genotype and HIV infection influence intracerebral inflammation and survival from tuberculous meningitis, Journal of Infectious Diseases, 2017 Apr 1. PMID: 28419368.
  10. Heemskerk AD, Bang ND, Mai NT, Chau TT, Phu NH, Loc PP, Chau NV, Hien TT, Dung NH, Lan NT, Lan NH, Lan NN, Phong le T, Vien NN, Hien NQ, Yen NT, Ha DT, Day JN, Caws M, Merson L, Thinh TT, Wolbers M, Thwaites GE, Farrar JJ. Intensified Antituberculosis Therapy in Adults with Tuberculous Meningitis. N Engl J Med.2016 Jan 14. PMID: 26760084.
  11. Nhu NT, Heemskerk D, Thu do DA, Chau TT, Mai NT, Nghia HD, Loc PP, Ha DT, Merson L, Thinh TT, Day J, Chau Nv, Wolbers M, Farrar J, Caws M. Evaluation of GeneXpertMTB/RIF for diagnosis of tuberculous meningitis. Journal of Clinical Microbiology. 2014. PMID: 24197880.
  12. Tobin DM, Roca FJ, Oh SF, McFarland R, Vickery TW, Ray JP, Ko DC, Zou Y, Bang ND, Chau TT, Vary JC, Hawn TR, Dunstan SJ, Farrar JJ, Thwaites GE, King MC, Serhan CN, Ramakrishnan. Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell. 2012. PMID: 22304914.
  13. Török ME, Yen NT, Chau TT, Mai NT, Phu NH, Mai PP, Dung NT, Chau NV, Bang ND, Tien NA, Minh NH, Hien NQ, Thai PV, Dong DT, Anh DT, Thoa NT, Hai NN, Lan NN, Lan NT, Quy HT, Dung NH, Hien TT, Chinh NT, Simmons CP, de Jong M, Wolbers M, Farrar JJ. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)—associated tuberculous meningitis. Clinical Infectious Diseases. 2011. PMID: 21596680.
  14. Caws M, Thwaites G, Dunstan S, Hawn TR, Lan NT, Thuong NT, Stepniewska K, Huyen MN, Bang ND, Loc TH, Gagneux S, van Soolingen D, Kremer K, van der Sande M, Small P, Anh PT, Chinh NT, Quy HT, Duyen NT, Tho DQ, Hieu NT, Torok E, Hien TT, Dung NH, Nhu NT, Duy PM, van Vinh Chau N, Farrar J. The influence of host and bacterial genotype on the development of disseminated disease with Mycobacterium tuberculosis. PloS Pathogens 2008 Mar 28, PMID: 18369480.
  15. Thwaites GE, Nguyen DB, Nguyen HD, Hoang TQ, Do TT, Nguyen TC, Nguyen QH, Nguyen TT, Nguyen NH, Nguyen TN, Nguyen NL, Nguyen HD, Vu NT, Cao HH, Tran TH, Pham PM, Nguyen TD, Stepniewska K, White NJ, Tran TH, Farrar JJ. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med.2004 Oct 21. PMID: 15496623.