Establishing and evaluating minimally invasive autopsy to determine cause of death from infectious disease in Vietnam

Pathology is the science of the causes and effects of diseases, especially the branch of medicine that deals with the laboratory examination of samples of body tissue for diagnostic or forensic purposes that have been obtained from an affected part of the body while the patient is alive (biopsy) or dead (necropsy or autopsy). In medicine, pathologic examination of tissues from patients who have died can be helpful to establish the cause of death. Knowledge of cause of death is of importance for prioritizing and distribution of public health resources. In Vietnam pathology is not part of routine diagnostics of patients and is not routinely used to establish cause of death. Knowledge of cause of death in Vietnam is therefore limited, also due to limited diagnostic capacity and inadequate national recording and reporting systems. In infectious diseases, which are the cause of death of around 10-15% of all people who die, the cause of death is only known in a minority of cases.

In the proposed project we aim to do three things.
1. To explore the attitudes towards postmortem investigations
2. To build pathology capacity in two large infectious diseases hospitals
3. To evaluate the use of a novel way of doing autopsies by only taking small samples using hollow needles from different sites of the human body. This is called minimally invasive autopsy (MIA).

Attitudes: A social scientist will explore the attitudes and perceptions towards postmortem investigations and sampling among a) the general public by inviting people to complete an online survey in a press release in national newspapers and b) healthcare professionals, religious leaders and patients relatives during focus group discussions. We will discuss postmortem investigations and sampling in general, and full autopsy and MIA in particular. We will show a video of both full and minimally invasive autopsies and ask participants to comment, to discuss their perceptions and beliefs regarding both procedures on a professional and personal level.
Capacity: Simultaneously, we will build capacity for pathology in the National Hospital for Tropical Diseases and Bach Mai Hospital in Hanoi. This will include purchase of necessary equipment and consumables for taking and analysing biopsy and MIA samples, training of Vietnamese clinical and laboratory staff by UK based pathologists and enabling implementation of pathology in routine clinical diagnostics, e.g. liver biopsy in infectious diseases of the liver
Evaluation: Evaluate the contribution of MIA to establish the cause of death in patients who have died from one of three infectious clinical syndromes: infection of the central nervous system (brain and spinal cord), of the lungs (pneumonia) and of the bloodstream (sepsis/septic shock). After obtaining permission from relatives, we will use the validated MIA protocols - adapted to be acceptable locally using information from the Attitude phase - to take samples from the deceased patient and we will use general and pathogen specific pathologic examination and highly sensitive molecular techniques that detect genetic information of almost all known infectious agents (next generation sequencing) to establish cause of death. We will do this on a total of 100 patients.

All OUCRU's work is made available in open-access publications, and will be presented at (inter)national conferences and at policy groups. Public Engagement (PE) activities will be designed and coordinated by the very active OUCRU PE team, working with project researchers and health workers in each site to implement and communicate these activities.

Knowledge of cause of death is an important public health metric to guide interventions and research. Infectious disease are estimated to contribute 10-15 % of all cause mortality in Vietnam but the exact aetiology of the cause of death in these cases remains unknown in the majority of patients. Diagnostic autopsy to establish cause of death is not part of standard of care and is rarely performed in Vietnam. Reasons for this are that most deaths occur outside the health system, there are no facilities for full autopsy, and there may be negative attitudes toward post-mortem examination due to religious and cultural traditions. Minimally invasive autopsy (MIA)), in which hollow needles are used to sample a selection of body fluids and organs, has been proposed as an alternative to full autopsy and a simplified standardized protocol was recently described and validated.

The project consists of three arms. Social scientists will explore the cultural sensitivities surrounding autopsy among community and religious leaders, healthcare professionals, and patients' relatives. Simultaneously, diagnostic pathology capacity building and implementation will be cerried out at the two hospital sites, overseen by a UK based pathologist. The results from the social sciences work will be used to construct a tailor-made consent procedure and MIA protocol for use in a Vietnamese context, after which we will evaluate the efficacy of MIA in establishing cause of death in a total of 100 patients with three infectious syndromes (central nervous system infection, respiratory infection and sepsis/septic shock) as compared to standard of care. We will use routine microbiology and pathology techniques including immunostaining, followed by specific molecular diagnostic assays and next generation sequencing (MiSeq) to establish an aetiological diagnosis.

Academic Impacts
Enhancing knowledge, innovative methodology and worldwide academic advancement
By using the innovative technique of Minimally Invasive Autopsy (MIA) in these three disease syndromes the study will bring a great deal of new knowledge concerning the causes of fatal encephalitis, sepsis and pneumonia. Although geographically limited to Vietnam by necessity, success with the methodology in itself will provide a template and stimulus for further work in the region and worldwide. The knowledge from the social science component will provide useful data and methodology for other settings, particularly those underpinned by Buddhist beliefs. All research output will be made available in open access peer reviewed journals and will be presented locally and internationally.

Training skilled researchers and improving teaching and learning
We have a proven track record of educating and supporting high quality scientists and expect to enroll one Vietnamese student in a PhD programme focusing on MIA. The lack of autopsy in Vietnam means that there is limited tissue available for medical education. Thus both data and tissue from autopsy will be an extremely useful teaching resource for Vietnamese undergraduate and postgraduate biomedical students. The laboratories themselves will be useful for training the next generation of pathologists and as a nidus for development of pathology throughout Vietnam.

Economic and Societal Impacts
Improving health and wellbeing, evidence based policy-making
Through improved evidence of the causes of death, the government and research community will be able to better focus their resources to the problems exposed potentially resulting in novel diagnostics, and therapeutics, appropriately directed epidemiological investigation and well informed policy directed at the problems exposed. In the medium term this will lead to improvements in health extending beyond Vietnam to the global population. Further pathology diagnostic services will enable more rapid diagnosis and staging of disease resulting in immediate improvements on a local and National level.

Changing organizational culture and practice
By demonstrating the feasibility, acceptability and utility of autopsy we will change health service practice to increase the opportunities for autopsy. Success in one part of Vietnam will soon be copied within Vietnam and regionally.

Enhancing research capacity, knowledge and skills; attracting R & D investment
We expect to train several pathologists in the new skills of the MIA procedure and analysis as well as enhancing their skills in the interpretation of biopsy histology. The pathology laboratories set up through the study in two hospitals in Vietnam will be able to engage in further research after the completion of the study, building on what has been discovered. New avenues for research and development that are reliant on these services being present will be opened. Examples include further research on chronic infectious hepatitis, where grading of inflammation and fibrosis through histological examination is key.

Increasing public engagement with research and related social issues
The issues around autopsy are emotive and we will be exploring these and the benefits of science with the public in the social science component of the study. Further public engagement through the very active public engagement programme already established at OUCRU will ensure that issues raised by the study are discussed with the community at large.