Tuberculosis

Summary of 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 Vietnam, 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% of TB cases are missed, misdiagnosed and untreated. This can result in death or prolonged illness with increased disease transmission, or the 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.

 

Summary of OUCRU TB research

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, treatment responses 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 adjunctive anti-inflammatory drugs. Patients’ LTA4H genotypes have been found regulate inflammation and can be used to predict survival. Ongoing studies in meningeal and pulmonary TB have similar 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 recognition of M. tuberculosis and regulation of the immune response. We are also conducting RNA sequencing on clinical samples to illuminate the pathogenesis of different forms of TB.

Transmission, Resistance and Tolerance: Modern Beijing strains of M. tuberculosis have recently increased significantly in Vietnam and shown greater transferability 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 currently active studies:

  1. Adjunctive corticosteroids for TB meningitis in HIV-infected adults in Vietnam and Indonesia
  2. Leukotriene A4 hydrolase stratified trial of adjunctive corticosteroids for HIV-uninfected adults with TB meningitis in Vietnam
  3. Shortened intensive anti-TB and anti-inflammatory (aspirin) for children with TB meningitis in Uganda, Vietnam, Zambia, Zimbabwe
  4. Prospective observational study of the host and bacterial determinants of outcome from multi-drug resistant pulmonary TB
  5. Using tryptophan metabolism and response to corticosteroids to define new therapeutic targets for TB meningitis patients in Vietnam and Indonesia (ULTIMATE project)
  6. Evaluation of new diagnostics for incident, active and recurrent TB; potentially applied as point-of-care diagnostics based on host protein and transcript response (ENDxTB project)
  7. Whole genome sequencing (WGS) for the rapid prediction of drug susceptibility in patients with suspected multi-drug resistant TB in Vietnam
  8. How patients get multi-drug resistant TB
  9. Linking genotype and (immune) phenotype in TBM & multi-drug resistant TB using RNAseq
  10. Genome-wide and phylogenetic analysis to identify bacterial genes associated with TB outcomes
  11. tuberculosis antibiotic tolerance of clinical strains
  12. Genetic prediction of drug resistance by WGS: 100,000 strains (CRyPTIC project)

 

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 and collaborating in some trials. 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
Timothy Walker, Wellcome Trust Research Fellow, research interests: how patients get multi-drug resistant TB
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
Lê Hồng Vân, Clinical Research Physician, PhD student, research interests: host determinants of treatment outcomes in multi-drug resistant pulmonary TB
Julie Huynh, Clinical Research Paediatrician, PhD student, diagnosis and treatment of TBM in children
Đỗ Đặng Anh Thư, Senior Research Assistant, Clinical TB diagnosis, strain isolation, drug sensitivity testing
Vũ Thị Ngọc Hà, Senior Research Assistant, Host and pathogen genotyping, bacterial whole genome sequencing, inflammatory response
Nguyễn Lê Hoài Bảo, Research Assistant
Trần Dinh Dinh, Research Assistant
Vũ Thị Mộng Dung, Research Assistant
Hoàng Thanh Hải, Research Assistant
Nguyễn Lê Quang, Research Assistant
Lê Phạm Tiến Triều, Research Assistant
Đặng Thanh Vân, Research Doctor
Nguyễn Thị Anh Thư, Research Doctor
Trần Thị Hồng Ny, Research Doctor
Kim Lan, Research Nurse
Nguyễn Tuấn Hiệp, Research Nurse
Nguyễn Thị Hậu, Research Nurse
Võ Thanh Sơn, Research Coordinator
Phan Thị Hồng Đào, Research Nurse
Nguyễn Quang Diệu, Research Doctor

 

Partnerships and Collaborations

  • Hospital for Tropical Diseases, Vietnam
  • Pham Ngoc Thach Hospital, Vietnam
  • Professor Nguyễn Viết Nhung, National Lung Hospital, Vietnam
  • Professor Derrick Crook, University of Oxford
  • Professor Michael Inouye, Baker Heart and Diabetes Institute, Australia
  • Professor Diana Gibb and MRC Clinical Trials Unit, UK
  • Professor Reinout van Crevel, Radboud University, The Netherlands
  • Professor Thomas Hawn, University of Washington, USA
  • Professor Babak Javid, University of California San Francisco, USA
  • Professor Mary-Claire King, University of Washington, USA
  • Professor Lallita Ramakrishnan, University of Cambridge, UK
  • Professor Joel Tarning, Pharmacology department of MORU, Thailand
  • Professor Gerhard Walzl, Stellenbosch University, South Africa
  • Professor Jayne Sutherland, MRC Unit The Gambia at LSHTM, Gambia

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 et alCID 2011); intensified TB therapy improves survival in INH-R TBM (Heemskerk et al NEJM 2016, Heemskerk et al CID 2017); phase 2 trial of adjunctive aspirin for TBM (Mai et al Elife 2018).
  • Improving diagnostic methods in TBM: We defined the use of GeneXpert MTB/RIF in diagnosis of TBM (Nhu et 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, Thao et al CID 2019) identified predictors for increased mortality. Xpert MTB/RIF Ultra for the diagnosis of TBM (Donovan et al Lancet ID 2020).
  • 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). Effect of bacterial burden on inflammatory response and outcome (Thuong et al JID & Hai et al Tuberculosis 2019).
  • Defining TB drug resistance and transmission: Associations between cell size and structure and drug resistance have been shown (Vijay et al Frontiers in Microbiology 2017 & 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); Sources of multi-drug resistance (Vijay et al CID 2020); Risk factors for poor treatment outcomes of multidrug-resistant TB (Van et al BMC 2020).

 

Top 5 Publications

  1. Trinh T B Tram, Vu T N Ha, Do D A Thu, Tran D Dinh, Hoang N Nhung, Nguyen T Hanh, Nguyen H Phu, Guy E Thwaites, Nguyen T T Thuong. Variations in Antimicrobial Activities of Human Monocyte-Derived Macrophage and Their Associations With Tuberculosis Clinical Manifestations. Front Cell Infect Microbiol. 2020 Oct 23; 10:586101. PMID: 33194825
  2. Vijay Srinivasan, Vu T N Ha, Dao N Vinh, Phan V K Thai, Dang T M Ha, Nguyen H Lan, Hoang T Hai, Timothy M Walker, Do D A Thu, Sarah J Dunstan, Guy E Thwaites, Philip M Ashton, Maxine Caws, Nguyen T T Thuong. Sources of multi-drug resistance in patients with previous isoniazid resistant tuberculosis identified using whole genome sequencing: A longitudinal cohort study. Clin Infect Dis. 2020 Mar 13; ciaa254. PMID: 32166306
  3. Van LH, Phu PT, Vinh DN, Son VT, Hanh NT, Nhat LTH, Lan NH, Vinh TV, Trang NTM, Ha DTM, Thwaites GE, Thuong NTT. Risk factors for poor treatment outcomes of 2266 multidrug-resistant tuberculosis cases in Ho Chi Minh City: a retrospective study. BMC Infect Dis. 2020 Feb 22; 20(1):164. PMID: 3208768
  4. Donovan J, Thu DDA, Phu NH, Dung VTM, Quang TP, Nghia HDT, Oanh PKN, Nhu TB, Chau NVV, Ha VTN, Hang VTT, Trinh DHK, Geskus RB, Tan LV, Thuong NTT, Thwaites GE. Xpert MTB/RIF Ultra versus Xpert MTB/RIF for the diagnosis of tuberculous meningitis: a prospective, randomised, diagnostic accuracy study. Lancet Infect Dis. 2020 Jan 7. pii: S1473-3099(19)30649-8. PMID: 31924551
  5. Hai HT, Vinh DN, Thu DDA, Hanh NT, Phu NH, Srinivasan V, Thwaites GE, Thuong NTT. Comparison of the Mycobacterium tuberculosis molecular bacterial load assay, microscopy and GeneXpert versus liquid culture for viable bacterial load quantification before and after starting pulmonary tuberculosis treatment. Tuberculosis (Edinb). 2019 Dec; 119:101864. PMID: 31568973