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Blood-samples. Credit: Antonio Mendes

Febrile Illness Evaluation in a Broad Range of Endemicities (FIEBRE)

FIEBRE aims to reveal leading causes of fever in sub-Saharan Africa and southeast Asia. What are the main infections causing fever in children and adults, and how should they be treated?

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About us

Rapid diagnostic testing for malaria has revealed that most febrile patients in Africa and Asia do not have malaria. FIEBRE will find out what they have and how to treat them.

Who we are

Funded by the UK Department for International Development, FIEBRE collaborators include LSHTM, Liverpool School of Tropical Medicine, Universities of Oxford, Barcelona and Otago, and partners in Laos, Malawi, Mozambique, Myanmar and Zimbabwe.

Publications

Study protocols, standard operating procedures, data collection tools and related materials will be made available as they are finalised and approved.

About
About FIEBRE

The objective of FIEBRE is to provide evidence:

  • on the most common infectious causes of fever;
  • on antibiotic susceptibility of bacterial causes;
  • on how local perceptions of fever affect treatment practices including the use of diagnostics and antimicrobial drugs;
  • to inform clinical guidelines and algorithms on how to manage non-malarial fevers.

The FIEBRE study will help to fill the gaps in evidence by means of a multi-centre study in countries with a high burden of infectious disease from which few or no data are available. The clinical and laboratory components of the study will focus on detecting infections that are treatable and/or preventable. Ethnographic work with community members, prescribers and public health workers will seek to understand how fever is understood by different communities of practice, and how this affects treatment practices.

The results will help to inform updated, evidence-based algorithms for the management of febrile illness, and provide data that may be used to design new diagnostics and rational approaches to disease surveillance. These outputs will ultimately help health systems and providers to provide more appropriate care to patients and lead to better clinical outcomes.

Who we are
Who we are FIEBRE

FIEBRE is funded by the UK Department for International Development. It is a multi-centre study conducted by the LSHTM, Liverpool School of Tropical Medicine, Barcelona Institute for Global Health (ISGlobal), Universities of Oxford and Otago, and partner institutions in Lao PDR, Malawi, Mozambique, Myanmar and Zimbabwe, and collaborating reference laboratories.

Partners

Country partners

Meet the team

LSHTM

Prof David Mabey, Principal Investigator
Dr Amit Bhasin, Programme Manager 
Dr John Bradley, Co-investigator, Statistician
Rebecca Handley, Research Assistant
Dr Heidi Hopkins, Co-investigator, Scientific Programme Coordinator 
Sham Lal, Co-investigator, Electronic Data Management System
Ruth Lorimer, Communications Officer 
Dr Chrissy Roberts, Co-investigator, ODK specialist and Laboratory Lead 
Karen Slater, Administrative support 
Dr Shunmay Yeung, Co-investigator, Paediatric Lead

Partner teams

The principal investigators for the partners are: 

Prof Quique Bassat, ISGlobal
Prof John Crump, University of Otago
Prof David Lalloo, LSTM
Prof Paul Newton, University of Oxford

For more details about each country team see the Where we work section.

Social science team

Dr Clare Chandler, Co-investigator, Social Science Lead
Dr Justin Dixon, Co-investigator, Social Scientist
Dr Coll Hutchison, Co-investigator, Social Scientist
Pat Ng, Project Manager, Social science team

Malawi
Eleanor MacPherson, Social Science lead (LSTM)
Chawanangwa Mahebere Chirambo, Social Science Co-lead and PhD Student
 
Myanmar
Yuzana Khine Zaw, PhD Student

Zimbabwe
Salome Manyau, Social Science Lead and PhD Student

Study governance

An External Advisory Committee (EAC) has been established to provide scientific oversight of the FIEBRE study. The members of the EAC are:

Prof Chris Whitty (Chair), Interim Government Chief Scientific Adviser & Professor of Public and International Health, London School of Hygiene & Tropical Medicine, UK
Dr David Meya, Associate Professor, College of Health Sciences, Makerere University, Uganda
Dr T Jacob John, Professor Emeritus, Christian Medical College, (CMC) Vellore, India
Dr Amanda Walsh, Senior Scientist, Emerging Infections and Zoonoses, National Infection Service, Public Health England, UK

Where we work
FIEBRE study sites

The FIEBRE study sites are in Laos, Malawi, Mozambique, Myanmar and Zimbabwe. 

Lao

Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU)

The Mahidol Oxford Tropical Medicine Research Unit (MORU) develops effective and practical means of diagnosing and treating malaria and other neglected diseases such as melioidosis, typhus, TB and leptospirosis. MORU was established in 1979 as a research collaboration between Mahidol University (Thailand), Oxford University (UK) and the Wellcome Trust UK. It is a network of a diversity of subunits including the Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Lao PDR (LOMWRU). This is a small clinical tropical medicine research group based at Mahosot Hospital, Vientiane. LOMWRU builds diagnostic, clinical and research capacity to help improve global, regional and Lao public health. LOMWRU’s main areas of research interest are in the diagnosis, epidemiology and treatment of malaria, rickettsial infections, leptospirosis, melioidosis, community-acquired septicaemia, central nervous system infections, the causes of acute fevers and public health aspects of medicine quality problems.  

Malawi

Malawi-Liverpool Wellcome Trust Research Programme (MLW)

The Malawi site will be Chikwawa district in the southern region of Malawi. Chikwawa district is 5,000 km2 with a population of 350,000 and is served by Chikwawa Hospital.  

The work will be based out of the Malawi-Liverpool Wellcome Trust Clinical Research Programme (MLW) . Established in 1995, MLW is an internationally-recognised health research institution led by Malawian and international scientists with the aim of improving the health of people in sub-Saharan Africa. MLW is built around laboratories, located at Queen Elizabeth Central Hospital, in Blantyre.  

The principal investigator is Dr Nicholas Feasey and the study doctor is Dr Ed Green.   

Mozambique

Centro de Investigacao em Saude de Manhica (CISM)

In Mozambique, FIEBRE is coordinated by the Centro de Investigação em Saúde da Manhiça (CISM) in collaboration with the Barcelona Institute of Global Health (IS Global). 

CISM was established in 1996 with the objective of conducting biomedical research in those diseases that affect the most poor and vulnerable. The Centre includes a fully equipped laboratory including parasitology, haematology, biochemistry, microbiology, (including biosafety level III premises), molecular biology (including PCR and RT-PCR) and immunology. CISM has been running a Demographic Surveillance System (DSS) since 1996, covering the whole district’s population and it set up a morbidity surveillance system at Manhiça District Hospital (MDH) in 1998. Overall, data on over 70,000 paediatric admissions and more than 1.2 million outpatient visits have been collected in the past 18 years. CISM’s other activities include: malaria screening, microbiological surveillance; pneumonia surveillance and conducting studies on issues with an important impact on public health policies in the country. 

The study will be conducted in the district of Manhiça (population 182,000 inhabitants, 2300 km2), a rural area located 90 km away from the capital Maputo. MDH acts as the referral health facility for the area. 

The study’s Principal Investigator at the site is Professor Quique Bassat, supported by co-investigators  Dr Marta Valente, Dr Antonio Sitoe, Dr Lola Madrid, Dr Rubao Bila, in addition to a larger team of Mozambican-based supporting staff.  

Myanmar

University of Medicine 1, Yangon

Researchers from the University of Medicine 1, Yangon, Myanmar, will be implementing research activities  for the FIEBRE study with colleagues at Thanlyin District Hospital through the longstanding University of Otago – University of Medicine 1 Collaboration. The research team will be based at Thanlyin District Hospital a busy district hospital in south Yangon. 

The Myanmar Principal Investigator is Professor Wah Win Htike, Professor and Head, Department of Microbiology, University of Medicine 1. She leads a team including Professor Hla Hla Win, Professor and Head, Department of Preventive and Social Medicine and Professor Zaw Lynn Aung, Professor and Head, Department of Medicine, University of Medicine 1. Dr Win Thandar Oo, a University of Medicine 1 medical microbiologist, will study towards a University of Otago PhD linked to the work at the Myanmar FIEBRE site.  

Professor John Crump, McKinlay Professor of Global Health and Co-Director of the Otago Global Health Institute, University of Otago, will support this work. Professor Crump has been instrumental in the design and development of the FIEBRE study, and has coordinated reference laboratory engagement. 

Zimbabwe

Biomedical Research and Training Institute (BRTI)

The researchers in Zimbabwe are based at the Biomedical Research and Training Institute (BRTI) in Harare. Established in 1995, the BRTI provides effective and professional research facilities including laboratory facilities for molecular diagnostics, micro-biology, serology, TB and immunology. BRTI aims to improve health and quality of life in Africa through conducting research and training. Its role is to provide the infrastructural support that researchers in all aspects of health need to become effective in influencing policy. 

The study site incorporates major hospitals in Harare (urban setting) Harare Central Hospital (HCH) and Chitungwiza Hospital. These hospitals have both inpatient and outpatients care of all age groups with patients referred from local clinics and provincial hospitals. The hospitals serve urban and peri-urban communities in southern Harare. In addition, outpatients will be recruited from polyclinics in south-western Harare.  

The BRTI team is led by Dr Katharina Kranzer (Principal investigator) with Professor Rashida Ferrand (Co-principal investigator) and comprises: Dr Ioana Olaru (Study coordinator), Ethel Dauya (Field manager), Tsitsi Bandason (Data manager), Salome Manyau (Social science lead), Beauty Makamure (Laboratory manager) and Tendai Muchena (Administrator). Partners include the Department of Medicine and Paediatrics at Harare Hospital and Chitungwiza Hospital, the University of Zimbabwe and Harare City Health Services.

Updates
Updates List Block
FIEBRE at ASTMH 2018

FIEBRE will be at the 67th Annual Meeting of the American Society of Tropical Medicine and Hygiene (ASTMH) which takes place from 28 October to 1 November 2018 in New Orleans.

Several FIEBRE colleagues are participating in a symposium:

100,000 papers later: Reviewing and mapping the etiology of non-malarial febrile illnesses globally

Session 39, 29 October 2018, 16:00-17:45 h

Organizer: Philippe J. Guerin, Infectious Diseases Data Observatory (IDDO)

More details available on the ASTMH website

A co-investigators meeting will also be held with representatives from many of the partners and organisations involved in the study taking the opportunity to discuss progress so far.

ASTMH annula meeting image
Patient enrolment starts in Laos and training takes place in Mozambique

FIEBRE is progressing well with three sites now enrolling participants and one prepared, ready to start.

October is a busy month with the London School of Hygiene & Tropical Medicine team travelling from Asia to Africa to hold training first in Laos then Mozambique.

The LOMWRU team in Laos, led by Dr Vilhada Chansamouth, enrolled their first patient at the Vientiane Provincial Hospital on 11 October 2018.

The background to this was several weeks' of training in all aspects of the study at the MORU office in Laos and at CISM Manhica, Mozambique. This includes reviewing SOPs, data input with ODK, sample taking with colleagues, consent procedures and labaratory management. A range of clinical, technical, data and labarotory staff are all involved.   

After gaining experience from previous training and pilot sessions in Zimbabwe and Malawi the activities were adapted to meet the needs of the teams, as all the facilities and personnel involved have different specialisms and knowledge.

Issues have arisen as enrolment is ongoing. Analysis has shown that excluding children with symptoms of cough/fast breathing (only outpatients) has significantly limited recruitment in Zimbabwe, with the potential to do so in Laos and Myanmar. Therefore amendments to the selection criteria have been made to address this.

Questions have also arisen over the definition of fever and methods used by staff (axillary or tympanic measurement of temperatures) for study enrolment, as a result, the SOP is being adjusted to aid enrolment.   

Training in Laos

The quick access to data through OpenDataKit from all sites enables such issues to be picked up swiftly, discussed and addressed to ensure the study continues to run smoothly, efficiently with consistency from country to country.

FIEBRE symposium

FIEBRE is holding a symposium during LSHTM week.

Fever, diagnosis and antimicrobials: the multi-disciplinary FIEBRE study 

Date: Monday, 17 September 2018    Time: 14.00–16.30 h
Where: Manson Theatre, London School of Hygiene & Tropical Medicine

The symposium will look at the challenges facing a large multi-disciplinary study taking place across sub-Saharan Africa and South East Asia.

The topics under discussion will be anthropology, paediatric and adult clinical care, antimicrobial resistance, standard and novel diagnostics, approaches to database management, project management and statistical issues.

This will be an opportunity to come along and find out about the latest data emerging from FIEBRE on the causes of fever, antimicrobial resistance, treatment seeking, case management and the roles of antibiotics.

Representatives from the Malaria Centre, AMR Centre and MARCH Centre will be presenting on several aspects of the study including: social science; clinical value of biomarkers; use of and experience of ODK to enable real-time data access; and recruitment of controls.

Speakers include: Shunmay Yeung; Heidi Hopkins; Clare Chandler; Sham Lal; John Bradley; Ioana Olaru and David Mabey. 

A recording of the event is available online

FIEBRE symposium flyer
First participant enrolled in Zimbabwe

The first patient was enrolled in the study on 22 June 2018 by the team at Biomedical Research and Training Institute (BRTI) in Harare.

The plan is to enrol 2400 febrile patients at each of five sites, over a 12-month period at each site to account for possible seasonal variation. The patients will include children and adults, both inpatients and outpatients. 

On the day of enrolment a venous blood sample is taken, a nasopharyngeal swab (to test for respiratory viruses) and in addition a urine sample from young children and patients of any age who have possible urinary tract infection symptoms. At the initial assessment stage, the team will, also undertake diagnostic tests (such as malaria tests and blood culture) that are of immediate clinical benefit to the patient, and for research purposes.

The focus of the study is on infections that are treatable and/or preventable. Participants will also be asked to return in 28 days’ time when a further blood sample will be taken for serology. Community control participants are also recruited to provide additional data for interpretation of diagnostic tests, and information on antimicrobial use in the surrounding communities.

Although fever is one of the most common presenting symptoms there have been few studies on its potential causes. FIEBRE will provide valuable data to help identify the causes of fever in settings where diagnosis is not usually available in real time, thus enhancing the quality of local care.

Recruitment of patients at the Malawi site in Chikwawa is due to begin in the coming weeks, following training sessions and collaborative work to refine data collection tools and to address site-specific logistical aspects. 

FIEBRE training starts in Zimbabwe and Malawi

Final FIEBRE study preparations are underway with formal staff training at the Biomedical Research and Training Institute (BRTI) in Harare. Staff from Malawi, Zimbabwe and LSHTM assembled for collaborative training, bringing together all components of the study: clinical, laboratory, social science, and data teams. The teams reviewed the study protocol, standard operating procedures (SOPs), and data forms, and discussed and practiced harmonised procedures for obtaining informed consent, collecting clinical and laboratory data, and obtaining samples from FIEBRE study participants.

The clinical team practiced recording information using the Open Data Kit (ODK) data entry system. The social science team joined clinical colleagues to share advice on administering aspects of study questionnaire.

Following training at BRTI, the LSHTM team moved on to Malawi to continue work and training with collaborators at the Malawi–Wellcome Trust’s (MLW’s) facilities. The collaborative work across sites is important to identify and address any potential issues before the study begins in earnest, and to ensure consistency between sites.

Demonstration of obtaining a nasopharyngeal swab
Demonstration of obtaining a nasopharyngeal swab

The FIEBRE scientific coordinator, Dr Heidi Hopkins, said, “The site staff have shown great teamwork, expertise, focus, and engagement during this training period in Zimbabwe and Malawi. Together, we’ve been able to identify and address many questions and challenges while beginning to operationalise the protocol on the ground. Pilot enrolment will begin at both sites as soon as a few final details are tucked in, and staff training in Laos, Mozambique and Myanmar is anticipated in coming weeks.”

Publications

Publications, research and data produced and contributed to by FIEBRE team members is available including:

  • Journal articles
  • Conferences, workshops and presentations
  • Books, chapters and sections
  • Seminars and lectures
  • Media
Publications List Block
The Consequences of AMR Education and Awareness Raising: Outputs, Outcomes, and Behavioural Impacts of an Antibiotic - Related Educational Activity in Lao PDR
Marco J. Haenssgen, Thipphaphone Xayavong, Nutcha Charoenboon, Penporn Warapikuptanun and Yuzana Khine Zaw
2018
Antibiotics 2018, 7(4), 95; DOI: 10.3390/antibiotics7040095
A comparison of patients' local conceptions of illness and medicines in the context of C-reactive protein biomarker testing in Chiang Rai and Yangon
Khine Zaw, Y., Charoenboon, N., Haenssgen, M. J., Lubell, Y. (2018)
2018
American Journal of Tropical Medicine and Hygiene
The social role of C-reactive protein point-of-care testing to guide antibiotic prescription in Northern Thailand
Haenssgen, M. J., Charoenboon, N., Althaus, T., Greer, R. C., Intralawan, D., & Lubell, Y. (2018).
2018
Social Science & Medicine, 202, 1-12. Epub 2018 Feb 23
It is time to give social research a voice to tackle antimicrobial resistance?
Haenssgen, M. J., Charoenboon, N., & Khine Zaw, Y. (2018)
2018
Journal of Antimicrobial Chemotherapy, Volume 73, Issue 4, 1 April 2018, Pages 1112–1113 doi.org/10.1093
Malaria-free but still sick: What’s giving millions of kids fevers?
Gretchen Vogel
2018
Science; doi:10.1126/science.aat5098
The epidemiology of febrile illness in sub-Saharan Africa: implications for diagnosis and management
Maze MJ, Bassat Q, Feasey NA, Mandomando I, Musicha P, Crump JA
2018
Clin Microbiol Infect. 2018 Feb 15 doi: 10.1016/j.cmi.2018.02.011
Addressing Antimicrobial Resistance Through Social Theory: An Anthropologically Oriented Report.
Chandler, C; Hutchinson, E; Hutchison, C
2016
Technical Report. London School of Hygiene & Tropical Medicine
Estimating the Burden of Febrile Illnesses
Crump JA, Kirk MD.
2015
PLoS Negl Trop Dis; 9(12): e0004040
Etiology of Severe Febrile Illness in Low- and Middle-Income Countries: A Systematic Review
Prasad N, Murdoch DR, Reyburn H, Crump JA.
2015
PLoS One; 10(6): e0127962
Etiology of severe non-malaria febrile illness in Northern Tanzania: a prospective cohort study
Crump JA, Morrissey AB, Nicholson WL, et al.
2013
PLoS Negl Trop Dis; 7(7): e2324
Causes of non-malarial fever in Laos: a prospective study
Mayxay M, Castonguay-Vanier J, Chansamouth V, et al.
2013
Lancet Glob Health; 1(1): e46-54
Estimating the incidence of typhoid fever and other febrile illnesses in developing countries
Crump JA, Youssef FG, Luby SP, et al.
2003
Emerg Infect Dis; 9(5): 539-44
Research and substudies

Other research, masters projects and sub-studies will take place in association with the main FIEBRE study, information about these is detailed in this section. 

Research and substudies

Marker of Severity Diagnostics for Evaluating Fever (MOS-DEF)

The Marker of Severity Diagnostics for Evaluating Fever (MOS-DEF) project is a sub-study of FIEBRE. The objective of MOS-DEF is to develop, evaluate and deploy multiplex assays to measure human blood-borne factors that are released during an immune response. These factors may be informative to indicate the potential causes of fever, and/or, the severity of fever.

Analysis of the assay data will take the form of statistical and computational approaches to identifying individual markers or combinations of markers that could assist in identifying the root cause of fever, the severity of disease in patients presenting with fever and 28 day outcomes of fever cases.

As a sub-study of FIEBRE, the source materials of MOS-DEF are blood plasma collected from inpatient and outpatient settings in the FIEBRE study countries. Analyses will be informed by pre-existing clinical and laboratory data collected during FIEBRE.

Tegwen Marlais is leading the MOS-DEF multiplex assay development at LSHTM.


Carriage of antimicrobial resistance genes in children enrolled in the FIEBRE study 

Antibiotic resistance (or antimicrobial resistance - AMR) is a well-recognised threat to global health. Few studies have examined how frequently people in Africa carry bacteria with genes that confer resistance to different antibiotics. The limited data available suggest that the rate of carriage of bacteria with resistant genes is high, even when the antibiotics in question are not widely available locally. There are unanswered questions as to where these genes have come from: previous antibiotic use (either prescribed or over-the-counter); environmentally from the hospital or community, or from eating food where antibiotics have been used in production. We also do not know how often carrying bacteria with AMR genes leads to disease, and whether this leads to a worse outcome for African children. 

This study aims to investigate how often children with fever attending inpatient and outpatient facilities in Zimbabwe carry AMR bacteria, whether this relates to the cause of their fever, and leads to worse outcome. The rates of AMR bacterial carriage will be compared before and after admission (for inpatients) and with community controls. In a small number of samples, I AMR genes within bacteria will be analysed and compared, to see if the spread of particular genes in hospitals and communities can be mapped, and to explore where the genes may have come from. This study is planned to produce initial data for a wider study in collaboration with vets and geographers looking at the spread of AMR genes in Zimbabwe, and what can be done to prevent that spread.

Photo of Felicity Fitzgerald

Project duration: 2017 – 2021

LSHTM lead investigator: Felicity Fitzgerald, UCL Great Ormond Street Institute of Child Health 
Coinvestigators: Rashida Ferrand, Shunmay Yeung, David Mabey, Ioana Olaru
Funding: Academy of Medical Sciences and the funders of the Starter Grant for Clinical Lecturers scheme
Location: Zimbabwe
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