As described by the CDC, “Infectious diseases whose incidence in humans has increased in the past 2 decades or threatens to increase in the near future have been defined as “emerging.” These diseases, which respect no national boundaries, include:
- New infections resulting from changes or evolution of existing organisms,
- Known infections spreading to new geographic areas or populations,
- Previously unrecognized infections appearing in areas undergoing ecologic transformation, and
- Old infections reemerging as a result of antimicrobial resistance in known agents or breakdowns in public health measures.”
The importance of emerging infections in Vietnam
More than half the world’s human population and three quarters of the world’s domesticated poultry and pigs live within a 4-hour flight from Ho Chi Minh City. Viet Nam and Asia are considered hotspots for the emergence of novel infections and drug resistance. Pandemic threats such as SARS-coronavirus and avian influenza viruses H5N1, H7N9 and enterovirus A71 have all emerged from this region where the intersection of urbanisation, globalisation, the human-animal interface and mass international travel poses a dynamic threat. Moreover, the metropolitan areas of Ho Chi Minh City and Ha Noi have daily large numbers of incoming flights from the region and other continents with associated possibilities of import and transmission of many emerging infections.
The translational potential of mass spectrometry and next-generation sequencing in patients with central nervous system infections in Vietnam
Central nervous system infections cause significant mortality and morbidity worldwide, but especially in low- and middle-income countries. According to the World Health Organization, Central nervous system infections caused ~35 million Disability Adjusted Life Years (DALYs) globally in 2012. Clinical outcomes are highly dependent upon the rapid identification of the causative agent and instituting effective (antimicrobial) therapy. However, current diagnostics are inadequate and the causative agent is identified in <50% of the patients. Furthermore, Southeast Asia (including Vietnam) is highly susceptible to vector-borne diseases (e.g. Japanese encephalitis and Zika virus), vaccine-preventable diseases (e.g. Streptococcus pneumoniae), multi-drug resistant organisms (e.g. Mycobacterium tuberculosis) and emerging novel pathogens (e.g. Nipah virus). New diagnostic approaches are urgently required for the rapid response to these evolving challenges and to improve patient outcomes.
We aim to answer three main research questions:
- Does cerebrospinal fluid contain discriminating protein/peptide signatures for the common bacterial, fungal and viral causes of Central nervous system infections?
- Can metagenomics detect a broad range of known/unknown pathogens in the cerebrospinal fluid, thereby improving upon current standard laboratory assays?
- Can next generation sequencing provide rapid whole-genome sequencing and prediction of antimicrobial susceptibility for tuberculosis and S. pneumoniae, the two commonest causes of bacterial meningitis worldwide?
Despite extensive diagnostic efforts the majority of severe infections (as sepsis and acute central nervous system infections) remains undiagnosed in routine clinical situations, but also in clinical studies with the aim to detect all known pathogens. For example, in clinical studies carried out by OUCRU in Viet Nam, between 20-40% of respiratory infections and 40-60% of central nervous system infections a pathogen could not be detected. This implies that there are still pathogens causing disease that we are unaware of, while South East Asia (including Vietnam) is predicted to be one of the hotspots of future emerging infections. Knowledge of which pathogens cause these severe diseases and building of local capacity that is capable of dealing with future emerging infections of unknown origins are important for both clinical management and public health interventions.
Our pathogen discovery programme aims to:
- Develop an in-house pipeline for sensitive and high throughput detection and characterization of (novel) pathogens
- Look for known/novel pathogens in clinical samples from undiagnosed patients with severe infections (acute central nervous system infections, respiratory infections and sepsis), and animal samples collected as part of the Wellcome Trust-Viet Nam Initiative on Zoonotic Infections (VIZIONS) project
Hand Foot and Mouth Disease
Hand, foot and mouth disease is an emerging infection of major public health significance in the Asia-Pacific region. Annually, hand, foot and mouth disease affects over two million children in Asia. In 2011 and 2012 Vietnam experienced two large outbreaks with over 200,000 children requiring hospitalization and over 200 deaths. Currently, there is no effective antiviral drug available to treat the infected patients, while vaccine has only been available for enterovirus A71, but its use is limited within China.
Some of the key questions we are trying to answer with our current clinical and laboratory research program on hand, foot and mouth disease:
- Which patients are at risk for development of severe disease and how can we recognize them early?
- Why do some patients develop very severe disease and is this a host or a pathogen phenomenon?
- Which viruses are associated with (severe) hand, foot and mouth disease, how do they evolve over time and how do they interact with the human immune system?
- What is the long-term outcome of very severe hand, foot and mouth disease?
- Are we using the right drugs to treat severe hand, foot and mouth disease patients?
- What are the costs-of-illness on patient and community level of hand, foot and mouth disease?
- What geographic, demographic and meteorological parameters are associated with hand, foot and mouth disease dynamics?
Clinical Research in outbreak situations
Clinical research, whether observational or interventional, has become an intrinsically slow process and the time from a completed protocol to the first enrolled patient could be up to two years for several reasons. This has been a major barrier to initiating clinical research in outbreak settings as was demonstrated during the 2009 pandemic of influenza (H1N1-pdm09). To address the need for change in our approach to research in these situations, OUCRU is collaborating with ISARIC, the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC).
Despite being a vaccine preventable disease, tetanus continues to be a problem in Vietnam. Tetanus is a severe disease where muscle spasm affects the whole body, eventually interfering with the ability to breath. In many countries, 50% or more people contracting tetanus will die because of this. Patients with tetanus need treatment in the intensive care unit for several weeks at least which also exposes them to other dangers such as hospital acquired infection with multidrug resistant organisms. We have been working with the Hospital for Tropical for Tropical Diseases on ways of improving tetanus treatment for over 20 years. We are working both on treating the disease better but also preventing it occurring. Our main questions are
- What are the best drugs to treat tetanus and how should they be given?
- Can we predict which patients will have most severe disease early on?
- Can we prevent problems associated with long intensive care unit treatment such as muscle wasting and hospital acquired infection?
- How can we improve vaccination coverage to reduce the numbers of patients acquiring tetanus?
Dr Le Van Tan, Group Head & Wellcome Trust International Intermediate Fellow
Dr Angela McBride, PhD student, Wellcome Trust Clinical PhD Fellow in Global Health
Ms Nguyen To Anh, PhD student
Dr Catherine Anscombe, Postdoctoral Fellow
Professor Dr Quang Ha, Virologist
Mr Phung Tran Huy Nhat, BSc, Research Assistant
Ms Nghiem My Ngoc, PhD student
Ms Nguyen Thi Thu Hong, MSc, Research Assistant
Ms Nguyen Thi Lieu, Nurse
Dr Louise Thwaites, Wellcome Research Career Re-entry Fellow
Dr Le Nguyen Thanh Nhan, PhD student
Ms Le Nguyen Truc Nhuc, MPhil, Research Assistant
Ms Lam Anh Nguyet, BSc, Research Assistant
Ms Nguyen Thi Han Ny, BSc, Research Assistant
Ms Do Duong Kim Han, Nurse
Dr Vu Thi Ty Hang, Postdoctoral Fellow
Ms Le Kim Thanh, Lab assistant
Dr Tran Tan Thanh, Postdoctoral Fellow
Ms Nguyen Thi Kha Tu, PhD student
Dr Hoang Minh Tu Van, Postdoctoral clinician Fellow
Dr Lam Minh Yen, Senior Clinician
Important publications from our group
- Nhan LNT, Hong NTT, Nhu LNT, Nguyet LA, Ny NTH, Thanh TT, Han DDK, Van HMT, Thwaites CL, Hien TT, Qui PT, Quang PV, Minh NNQ, van Doorn HR, Khanh TH, Chau NVV, Thwaites G, Hung NT, Le VT. Severe enterovirus A71 associated hand, foot and mouth disease, Vietnam, 2018: preliminary report of an impending outbreak. Euro Surveill. 2018 Nov;23(46). PMCID: PMC6247458.
- T Anh, LNT Nhu, HMT Van, NTT Hong, TT Thanh, VTT Hang, NTH Ny, LA Nguyet, TTL Phuong, LNT Nhan, NT Hung, TH Khanh, HM Tuan, HL Viet, NT Nam, DC Viet, PT Qui, B Wills, S Sabanathan, NVV Chau, L Thwaites, HR van Doorn, G Thwaites, MA Rabaa, and LV Tan, Emerging Coxsackievirus A6 Causing Hand, Foot and Mouth Disease, Vietnam, Emerging Infectious Diseases, 2018. PMCID: PMC5875260
- Anh NT, Hong NTT, Nhu LNT, Thanh TT, Anscombe C, Chau LN, Thanh TTT, Lau CY, Limmathurotsakul D, Chau NVV, Rogier van Doorn H, Deng X, Rahman M, Delwart E, Le T, Thwaites G, Van Tan L; Southeast Asia Infectious Disease Clinical Research Network. Detection and Characterization of Human Pegivirus 2, Vietnam. Emerg Infect Dis. 2018 Nov;24(11):2063-2067. PMCID: PMC6199981.
- Rudd KE, Seymour CW, Aluisio AR, Augustin ME, Bagenda DS, Beane A, Byiringiro JC, Chang CH, Colas LN, Day NPJ, De Silva AP, Dondorp AM, Dünser MW, Faiz MA, Grant DS, Haniffa R, Van Hao N, Kennedy JN, Levine AC, Limmathurotsakul D, Mohanty S, Nosten F, Papali A, Patterson AJ, Schieffelin JS, Shaffer JG, Thuy DB, Thwaites CL, Urayeneza O, White NJ, West TE, Angus DC; Sepsis Assessment and Identification in Low Resource Settings (SAILORS) Collaboration. Association of the Quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) Score With Excess Hospital Mortality in Adults With Suspected Infection in Low- and Middle-Income Countries. JAMA. 2018 Jun 5;319(21):2202-2211. PMCID: PMC6134436.
- NTH Mai, NH Phu, LNT Nhu, NTT Hong, NHH Hanh, LA Nguyet, TM Phuong, A McBride, DQ Ha, HDT Nghia, NVV Chau, G Thwaites and LV Tan, Central nervous system infection diagnosis by next generation sequencing: a glimpse into the future? Open Forum Infectious Diseases, 2017, PMCID: PMC5411956.
- A McBride, TTH Chau, NTT Hong, NTH Mai, NT Anh, TT Thanh, TT Van, LT Xuan, TPM Sieu, LH Thai, LV Chuong, DX Sinh, ND Phong, NH Phu, J Day, HDT Nghia, TT Hien, NVV Chau, G Thwaites, LV Tan, Angiostrongylus cantonensis is an Important Cause of Eosinophilic Meningitis in Southern Vietnam, Clinical Infectious Diseases, 2017, PMCID: PMC5447893.
- DB Thuy, JI Campbell, TT Thanh, CTh Thuy, HT Loan, LM Yen, LV Tan, MF Boni, CL Thwaites, Tetanus in Southern Vietnam: Current Situation, American Journal of Tropical Medicine and Hygiene, 2017, PMCID: PMC5239717.
- NT Anh, TT Thanh, HMT Van, NM Ngoc, LNT Nhu, LTM Thanh, PT Qui, TH Khanh, LNT Nhan, HL Viet, DC Viet, H.M. Tuan, NT Hung, NVV Chau, G Thwaites and LV Tan, Development and evaluation of a non-ribosomal random PCR and next-generation sequencing based assay for detection and sequencing of hand, foot and mouth disease pathogens, Virology Journal, 2016, PMCID: PMC4937578.
- V Tan, HR van Doorn, HD Nghia, TT Chau, TP Tu le, M de Vries, M Canuti, M Deijs, MF Jebbink, S Baker, et al., Identification of a new cyclovirus in cerebrospinal fluid of patients with acute central nervous system infections. MBio, 2013. 4(3): p. e00231-13, PMCID: PMC3684831.
- The South East Asian Infectious Disease Clinical Research Network (SEAICRN). Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial. BMJ. 2013; 346:f3039.