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.
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 and Zimbabwe.
Study protocols, standard operating procedures, data collection tools and related materials will be made available as they are finalised and approved.
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.
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 and Zimbabwe, and collaborating reference laboratories.
- ISGlobal – Barcelona Institute of Global Health
- Liverpool School of Tropical Medicine (LSTM)
- University of Otago, New Zealand
- University of Oxford
- Lao - Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU)
- Malawi - Malawi-Liverpool Wellcome Trust Research Programme (MLW)
- Mozambique - Centro de Investigacao em Saude de Manhica (CISM)
- Zimbabwe - Biomedical Research and Training Institute (BRTI)
Meet the team
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
The principal investigators for the partners are:
For more details about each country team see the Where we work section.
Social science team
Prof 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
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
The FIEBRE study sites are in Laos, Malawi, Mozambique and Zimbabwe.
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.
The main study site is Vientiane provincial hospital, a 100-bed hospital approximately 70 km from Mahosot Hospital. The team consists three study doctors and two laboratory technicians. The principal investigator is Dr Mayfong Mayxay.
The Malawi site is in 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 District Hospital.
The work is 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.
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 is being 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 and Dr Pio Vitorino, in addition to a larger team of Mozambican-based staff: Dr Nelson Tembe; Dr Sozinho Acácio; Dr Ajanovic Andelic, Campos Mucasse (Project manager); Vânia Afuale (Project assistant); Humberto Mucasse (Field coordinator); Teodimiro Matsena (Data manager); Anelsio Cossa (Laboratory coordinator); Manuel Muamede (Adult nurse coordinator); and Ilídio Cherinda (Paediatric nurse coordinator).
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.
The second FIEBRE Annual co-investigators meeting was held in Zimbabwe from 3 - 6 December 2018. World-leading fever experts were involved in the meeting contributing to the discussions and plans for the study going forward.
Over 40 team members of the partner organisations attended the meeting including London School of Hygiene & Tropical Medicine, Liverpool School of Tropical Medicine, Barcelona Institute for Global Health (ISGlobal), Universities of Oxford and Otago, Centro de Investigacao em Saude de Manhica, Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit , Malawi-Liverpool Wellcome Trust Research Programme and the Mahidol Oxford Tropical Medicine Research Unit.
The Biomedical Training and Research Institute (BRTI) hosted the event attended by representatives from all aspects of the study - laboratory, technical, data, clinical, microbiology and social science.
There was a packed agenda covering:
- Country updates - site and personnel details, number of patients and controls recruited, logistical recruitment challenges
- Solutions to ethical and operational issues
- Open Data Kit
- Laboratory activities
- Update on protocol amendments and implications of the changes
- Reference laboratories
- Microbiology data and interim analysis
- Social science update on overall research questions and initial findings from fieldwork
- Complementary studies
- Dissemination of results
- Way forward, follow-on studies and future plans
A visit to the Harare sites, Budiriro polyclinic, Chitungwiza General Hospital and Harare Central Hospital, and to the BRTI facilities, illustrated how the study proceeds from the initial recruitment of patients through data input to the samples being tested at the laboratory.
The social science team held a subsequent meeting from 7-8 December to look at their progress and analyse the data collected so far.
The meetings were successful and resulted in detailed plans for the study's future.
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.
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.
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 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.
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.
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.
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.”
The study documentation is available in this section including protocols, standard operating procedures and case report forms (CRFs).
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
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.
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.
Antimicrobial resistance of Gram-negative bacteria from urine specimens (ARGUS)
Antimicrobial resistance (AMR) is a global problem affecting all countries irrespective of income and geographical location, and has been highlighted by the World Health Organization as one of the three most important public health threats of the 21st century. The increase in AMR is driven among others by inappropriate antibiotic use, insufficient or lacking infection control systems and the dissemination of successful bacterial clones harbouring resistance genes. Infections due to drug-resistant organisms are associated with increased mortality and risk of onward transmission, particularly in low-income settings where alternative antibiotics are not readily available, and pose an immense burden on weak health systems.
The ARGUS study aims to investigate the prevalence of and underlying molecular mechanisms for AMR in Gram-negative bacilli causing urinary tract infections in Zimbabwe. Taking into account that inappropriate antibiotic use is a main driver of AMR, this study plans to investigate antibiotic consumption in adults presenting to primary care. This information may be used to interpret the results on prevalence of antibiotic resistance.
The results from this study will be used to inform policy and development of treatment recommendations. Whole genome sequencing results will provide a better understanding of the prevalent resistance genes in Zimbabwe, of the spread of successful clones, and potentially will contribute to developing strategies to tackle AMR.
Lead investigator: Dr Ioana Olaru is an infectious diseases physician and currently undertaking a PhD with LSHTM
Setting: primary care clinics from Harare
Population: 1500 participants with suspected urinary tract infections
Supervisors: Katharina Kranzer, Rashida Ferrand, Shunmay Yeung
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.
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