SouthEast Asia encephalitis - SEAe

Last update: 17 October 2013

Reduce the morbidity and mortality associated to infectious encephalitis in Southeast Asia by improving diagnosis and medical care for patients.

Project dates: 2012-2017

Context

Encephalitis is defined as an acute inflammation of the central nervous system associated with neurologic dysfunction. The most common etiologies are infections by either viruses or bacteria although parasites and fungi can also be occasionally detected, especially in immunocompromised patients. Because of high mortality and long-term neurological sequelae, encephalitis is of public health concern worldwide (Mailles et al., 2012). Reported incidences range between 3.5 and 7.4 cases per 100,000 patient-years with higher incidences in children than adults (Granerod and Crowcroft, 2007; Jmor et al., 2008). Various encephalitis outbreaks have recently emerged in Asia such as the fatal outbreak of enterovirus 71 (EV71) that occurred in mid-2012 in Cambodia affecting very young children (most below 3 years, all below 12 years). In Asia where many of the possible etiologies are of major public health concerns (i.e. dengue, Japanese encephalitis, West Nile virus, EV71), acute encephalitis is among the most frequent and severe causes of pediatric hospitalization (Wills and Farrar, 2000).

Despite extensive microbiological investigations and the use of the most advanced molecular biology-based assays, no pathogen is identified for a significant proportion of encephalitis patients in both industrialized and developing countries (28–85% of cases remain unconfirmed) (Jmor et al., 2008). Previous studies support the hypothesis that unknown and sometimes new emerging infectious agents may be responsible for cases of currently unknown etiology and strongly argue for an intensive effort to identify and characterize them (Granerod et al., 2010). This hypothesis is also strengthened by the recent apparent increase in emerging infectious diseases , many of which have been linked to human activities that impact the environment and to the spreading of pathogens to new geographic regions (Granerod et al., 2010; Smith and Guégan, 2010). From this perspective, the Southeast Asian region, a particularly significant biodiversity hotspot, is at high risk for new pathogen emergence. Indeed, growing human populations, increasing urbanization and frequent contact with wildlife and domesticated animals have created novel opportunities for the emergence of pathogens such as SARS at the end of 2002, and highly facilitated the spread of infectious diseases such as H5N1 high - pathogenicity avian influenza virus since 2004, and H1N1 pandemic influenza virus in 2009. The population in developing Southeast Asian countries is particularly at risk for the circulation of emerging or reemerging infectious agents and for this reason the surveillance and investigation of acute encephalitis syndrome in this region is of utmost public health importance, both locally and globally.

Surveillance and diagnostic capabilities for encephalitis remain poor and still suffer from serious shortcomings in most Southeast Asian countries and beyond. Although the burden of non-infectious encephalitis in this region remains to be ascertained, the best laboratories only identify etiological infective agents in less than half of patients. Moreover, because of the absence of reliable microbiological diagnostic capacity in the majority of public referral hospitals, local clinicians have to treat acute encephalitis syndromes mostly empirically, with little evaluation of the effectiveness of their clinical approach. Even if some of the most common causes of acute encephalitis syndrome may be vaccine-preventable, systematic data regarding the contribution of these diseases are lacking and no reliable data are available to define the burden of these infections, to describe the full clinical spectrum and characteristics of acute central nervous system infections, and to develop diagnostic and therapeutic algorithms to improve patient care. Besides, whatever the nature and magnitude of the encephalitis burden in Southeast Asia and the criteria used to assess it (i.e. morbidity, mortality, handicap, impact on families’ budget or livelihood), this burden is borne principally by underprivileged populations with limited access to prevention and health care.

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1. The definition of an emerging infectious disease identifies seven potential pathways by which a pathogen can emerge: (i) increasing in incidence (e.g. Lyme Disease), (ii) increasing in impact (e.g. Tuberculosis), (iii) increasing in geographic range (e.g. West Nile virus), (iv) evolving into a new pathogen (e.g. new strains of Influenza virus), (v) entering the human population for the first time (e.g. Nipah virus), (vi) significantly changing pathology or clinical presentation (e.g. Hantavirus Pulmonary Syndrome), or (vii) because they are newly discovered (e.g. Hendra virus) (Smith and Guégan, 2010).

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Objectives

The SEAe project specific objectives are:

  • To fill-in the biomedical knowledge gaps regarding acute encephalitis syndrome;
  • To strengthen hospital laboratories capacities to enhance health by improving diagnosis and care for patients;
  • To identify unknown pathogens responsible for encephalitis;
  • To document and analyze factors related to clusters of encephalitis cases integrating human health, animal health and environment through a "One Health" approach;
  • To provide reliable information and a sustainable regional and sub-regional surveillance network to clinicians and public health stakeholders that will help them to better define prevention policies, vaccination strategy, and build preparedness to emerging infectious risks.

Activities and Results

The project implementation will first start with three selected pediatric clinical sites in Cambodia (Kantha Bopha IV Children’s Hospital in Phnom Penh), Lao PDR (Mahosot Hospital in Vientiane) and Vietnam (Central Children’s Hospital in Hanoi), and will subsequently be extended to other ones.

The SEAe project has been structured around the following three interlinked workpackages (WP) to address the project’s aims using an integrated approach:

WP1, focused on clinical and epidemiological studies, will be responsible for the rigorous identification and inclusion of infectious encephalitis cases, the collection and storage of clinical data and biological samples to inform microbiological diagnosis. Training of medical personnel in clinical sites participating to the study will be an important aspect of the WP1 mission. Identification of clusters of cases unusual by their numbers, the causative pathogen, or the clinical presentation, will trigger field investigations conducted in collaboration with the WP3 teams. The prospective follow-up of survivors one year after discharge will document the long-term neuropsychic sequelae associated with acute encephalitis. The incidence of encephalitis caused by the etiological agents identified in WP2 will be estimated upon reliable and detailed data.

WP2, dedicated to the laboratory diagnosis, will improve the microbiological diagnosis of known pathogens by strengthening capacities in selected clinical sites and national collaborative centers, in order to provide the clinicians with state-of-the-art and timely laboratory diagnosis for the microorganisms accessible to treatment. In order to establish a harmonized diagnostic strategy, molecular diagnostic tools will be implemented allowing the detection and the study of the main infectious agents responsible for central nervous system in Southeast Asia. This workpackage will also include the detection and characterization of new or unusual pathogens in the samples of unknown etiology by using a combined approach: pan-generic PCRs, cell cultures, electron microscopy, High Throughput Sequencing (HTS).

WP3 will document and analyze collective and environmental risk factors related to cases in order to improve the understanding of human infectious encephalitis epidemiology in Southeast Asia, integrating potential environmental, epidemiological and sociological factors, and provide adapted surveillance, control and outbreak investigation methodologies. Indeed, recognizing the essential link between human, animal (domestic animal and wildlife) and environmental health, and the threat of disease transmission, field investigations will require an interdisciplinary approach – the "One Health" approach.

Transversal management activities and scientific coordination will be provided throughout the project in order to achieve the objectives.

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Partners

The proposed project is an ambitious and multidisciplinary research consortium associating:

(i) national health authorities in Cambodia, Lao PDR, Vietnam, Thailand and Indonesia;

(ii) local major university and clinical sites (national hospitals and provincial health centers); 

(iii) key French stakeholders of life and health sciences with research activities carried out in the Southeast Asian region such as: 

(iv) teams from the Southeast Asian Wellcome Trust Oxford University Major Overseas Programme. 

Collaborators

Principal Investigator Committee

The Principal Investigator Committee consists of three (3) members with no hierarchical link between them. The Principal Investigator Committee role and responsibilities may be divided into two related but distinctly different sets of activities: those activities involving the scientific direction of each of the three workpackages, and the regional promotion of the project among the funders and local authorities.

  • Marc Lecuit – Biology of Infection Unit, Institut Pasteur – U1117, Institut national de la santé et de la recherche médicale (Inserm) – National Reference Centre / WHO Collaborative Centre for Listeria – Department of Infectious Diseases and Tropical Medicine, Necker-Enfants Malades University Hospital, Paris Diderot University, Sorbonne Paris Cité, Institut Imagine, Paris, France
  • Paul Newton – Lao - Oxford - Mahosot Hospital - Wellcome Trust - Research Unit (LOMWRU), Vientiane, Lao PDR
  • Ronello Abila – OIE (World Organization for Animal Health) Sub-Regional Representation for Southeast Asia, Bangkok, Thailand

Scientific Advisory Board

The Scientific Advisory Board consists of five (5) international leading experts in areas of interest for the Project. The Scientific Advisory Board main responsibilities are to assist, guide and advise the Steering Committee on the running of the SEAe project and on other specific issues.

  • Antoine Gessain – Oncogenic Virus Epidemiology and Pathophysiology - CNRS URA 3015, Institut Pasteur, Paris, France
  • Christian Drosten – Institute of Virology, University of Bonn Medical Centre, Bonn, Germany
  • Benoît Durand – Animal Health Laboratory, French Agency for Food, Environmental and Occupational Health Safety (ANSES), Maisons-Alfort, France
  • Tom Solomon – Brain Infections Group, Department of Clinical Infection, Microbiology and Immunology, Institute of Global Health and Infection, University of Liverpool, United Kingdom
  • Fifth expert – to be further determined

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Last update: 17 October 2013

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