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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 Barcelona, Oxford and Otago, and partners in Laos, Malawi, Mozambique 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
Team photo Zimbabwe 2018

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.

Partners

Country partners

Meet the team

LSHTM

Prof David Mabey, Principal Investigator
Michael Lawrence, 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
Dr Mayfong Mayxay, LOMWRU 
Prof Paul Newton, University of Oxford

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

Malawi
Eleanor MacPherson, Social Science lead (LSTM)
 
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 and Zimbabwe. 

Laos

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.  

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 Assoc Prof Mayfong Mayxay with Dr Elizabeth Ashley and Prof Paul Newton as co-investigators.

Malawi

Malawi-Liverpool Wellcome Trust Research Programme (MLW)

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 study is taking place in Chikwawa District Hospital and a second site at St Montfort Hospital, Ngabu 30 km away has been opened up to help increase inpatient recruitment. 

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.  

The principal investigator is Prof 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 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).

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 are being recruited from Glen View and Rutsanana 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 ECTMIH 2019

FIEBRE will attending the 11th European Congress on Tropical Medicine and International Health (ECTMIH) from 16-20 September 2019 in Liverpool, UK.

Members of the team will be presenting on two topics:

  • FIEBRE (Febrile Illness Evaluation in a Broad Range of Endemicities): a multi-site prospective observational study of causes of fever in sub-Saharan Africa and Southeast Asia
    Hopkins H, Bassat Q, Chandler CIR, Crump JA, Feasey NA, Ferrand RA, Lalloo DG, Mayxay M, Newton PN, Mabey DCW
  • Emergence of diminished ciprofloxacin-susceptibility Salmonella typhi in an ongoing outbreak from Harare, Zimbabwe
    Ioana D Olaru, Nicholas Feasey, Rashida Ferrand, David Mabey, Heidi Hopkins, Sekesai Zinyowera, Ben Amos, Katharina Kranzer
ECTMIH logo
Malawi reaches 1000 patients and marks its 1 year anniversary

In Malawi, the first patient was enrolled on 4 July 2018; their 1000th patient, a child outpatient, was signed up at Chikwawa District Hospital on 11 June 2019. 

The Malawi-Liverpool Wellcome Trust Research Programme (MLW) team initially comprised 11 front line staff, working at Chikwawa District Hospital, rising to 15 in April 2019, as the second site in Ngabu, was opened to speed up inpatient recruitment, and weekend work started. The laboratory and freezers, where samples are further tested and stored, are based at MLW in Blantyre. 

Community engagement is integral to the study's success. FIEBRE has been helped by earlier community sensitisation work in the area. Two of the original fieldworkers are very well known and trusted in the community which has aided acceptance of the study. Before and during the study, there are regular engagement activities with the local community, including meetings with the district council where the local chiefs and villagers ask questions about the study. There's been particular interest and concern about the amount of blood taken (shown to a certain extent in some difficulties with getting blood samples from controls). Issues such as this are addressed by the team and their continued dedication in working with the local community. 
 
Chikwawa district and the Chikwawa district hospital are resource poor and constitute one of the most deprived areas and facilities in the country. The hospital is situated by the Shire river, in a largely rural district. In March, the study had to close for a week due to severe floods. The main road was washed away and one of the villages was badly affected with scores of homes washed away. Many of these people are living in temporary shelters and awaiting support for new homes to be built.  The situation was further compounded by Cyclone Idai causing flash floods shortly afterwards. St Montfort Hospital the second site is 30 km away from Chikwawa. This hospital is located in the major town in the district which services the main employer: Illovo Sugar.

In these settings, the FIEBRE team have been able to help support and add to the overall level of care and treatment in the area.  Moreover, a clinical microbiology and blood culture service has been provided enabling FIEBRE to contribute to the clinical diagnostic capacity at these hospitals. Even patients not on the study can access this service. Six cases of TB have been diagnosed in patients who otherwise would not have been diagnosed. This is likely to have been life-saving for some. There have been 16 positive blood cultures indicating septicaemia or blood poisoning. This is often fatal but thus far the patients have survived demonstrating further benefits to the community. 

Data for the year shows almost 4700 patients have been screened with about 1100 recruited. Loss to 28-day follow-up is at 7%, which reflects the good work of the team, as it can be challenging with inpatients as some reside outside the usual catchment area.
 

Malawi photo collage
Zimbabwe a year in, 1000 participants and counting

A year ago, the BRTI team in Zimbabwe started recruiting patients for FIEBRE. The first participant signed up for the study was a child outpatient enrolled on 22 June 2018. Since then more than 1000 participants have been recruited from five clinics across Harare and Chitungwiza. The team has diagnosed a large number of typhoid fever cases and collected invaluable data about the extent of antimicrobial resistance. Patients have received life-saving treatment that otherwise they may have had difficulties in accessing. FIEBRE has contributed to the clinical diagnostic capacity at these sites and also to regional antimicrobial resistance surveillance efforts.

Our dedicated field staff, comprising eight nurses and six research assistants, are currently working in two major hospitals (Harare Central and Chitungwiza General), three primary care clinics (Budiriro, Glen View and Rutsanana Polyclinics) and their surrounding communities. Three MSc students (two from LSHTM and one from University of Oxford) are helping with various aspects of the study. Felicity Aiano is working with the social science team; Michael Blank is working in the laboratory on the ARGUS study; and Zay Yar Aung has been investigating antimicrobial prescribing at Budiriro clinic.

The latest data show out of almost 1800 patients screened, 1038 were enrolled. The reasons for ineligibility vary and are monitored to establish if there are steps that can be taken to aid recruitment such as encouraging patients to consent through raising local community awareness of the study and its potential benefits. The amendment to the protocol to discard 'elevated respiratory rate' and 'cough' as an exclusion criterion for outpatients <15 years has helped recruitment in this category. Outpatient recruitment has gradually increased, particularly with the opening up of new sites in April. Control recruitment has been steady (67% of selected outpatients have been matched and recruited). The loss to follow up for Day 28 recruitment is low with 92% of patients having a Day 28 visit.

Collage of Zimbabwe photos
A long trip in Laos

Recruiting a community control is not not as simple as it seems. There's many stages involved behind the scenes as community controls must be frequency matched to the cases by age, sex, seasonality and geographical area. These data are calculated by the team at LSHTM. The LOMWRU team in Laos then spends a considerable amount of time and effort travelling long distances to locate and ask healthy individuals to take part in the study as community controls. 

Dr Somvai Singha produced a video of one such trip, which took 2 hours by motorbike and boat, to a village in Viengchan province 90 km away from the capital Vientiane. This shows the lengths people will go to seek care, the same journey can take 4 hours by road. 

Watch this fascinating video of a journey to locate a control:

 

A view from Malawi

Read about a study participant's experience in Malawi.

Fletcher Nangupeta and Frank Mlumbe, FIEBRE fieldworkers, organised a visit to meet two FIEBRE study participants, a mother and daughter, and the village elder, at William village, in Chikwawa district. The mother explained how her daughter had been enrolled in the study when she had presented with a fever, how the daughter had recovered after treatment and subsequently, when the mother herself became ill with a fever, she had no hesitation in taking part. 

FIEBRE in practice: Malawi FIEBRE visit to William village, T/A Katunga 
Report produced by Fletcher Nangupeta and Frank Mbalume

On 8 February 2019, we received three visitors from London School of Hygiene & Tropical Medicine namely; Amit Bhasin, Ruth Lorimer and Rebecca Handley. Staff from the Malawi Liverpool Wellcome Trust Research Programme (MLW) were also in attendance: Edward Green, Kate Haigh, Fletcher Nangupeta and Frank Mlumbe
We visited William village, in the traditional authority (T/A) area of Katunga, where we went to the house of a FIEBRE study participant. The main purpose of the visit was to find out what she understood about the study and to see how people in the community perceived the FIEBRE study. On arrival at the village, we were received by the village headwoman herself, the participant and her children. The team was introduced to both the participant and the village headwoman.
When she was asked about how she feels taking part in the study, she said ‘’it is a good experience to participate in the study, this is my second time taking part in the study and two of my children also took part in study”. She appreciated that now she knows the status of her body and the general health of the children. When asked about the blood volume and blood stealing myths which can occur in Malawi, she said, ‘’The myths were circulating sometime ago but nowadays people realise the importance of being in the study”. One inquisitive neighbour had enquired about FIEBRE: a lady from a village nearby who came and asked her if any of her children became sick or were weak after participating in the study and having their blood taken. She assured the lady that the child would be fine and she should not get worried. 
The team was interested in what people in the village do when they get sick; the participant and the village headwoman explained that a few individuals buy medicine mainly painkillers from within village shops while many of them go to the hospital when they became sick.
The team asked about the demographic and ethnic composition of the village. The village headwoman said that there are about 300 households in the village mainly headed by males apart from few households which are headed by females and children, and majority of them are from the Mang’anja tribe. The majority of the inhabitants of William village rely on farming as their main economic activity almost every household has a piece of land for farming and others keep livestock such as cattle, goats and chicken. Apart from farming, a few individuals have other jobs while others have small scale businesses.
One of the visitors asked how the village had changed over the years. The participant said that in the past most of the houses were grass thatched whereas now people are able to build iron-roofed houses, and people used to drink water from the wells and river and needed to walk long distances to get water, but now water comes from taps and boreholes.
The meeting concluded after approximately one hour with friendly farewells and handshakes. 

Team visit to William village

Meeting with FIEBRE participants and village elder

Four countries up and running

All four sites, Laos, Malawi, Mozambique and Zimbabwe, are now operating fully recruiting both adult and children out- and inpatients. 

The team at Centro de Investigação em Saúde de Manhiça (CISM) in Mozambique began enrolling adult patients at Manhiça Health Research Centre in mid-March after paediatric recruitment started in December 2019.

Two sites have now recruited over 500 patients. In January, Zimbabwe became the second site following Malawi. To enable enrolment of the full cohort expansion is under way in Malawi and Zimbabwe where nurses and research assistants have been taken on to recruit participants at new sites. The plan is to train staff and be ready to open up the new sites in April. 

All sites receive regular recruitment reports tailored to their specific data requirements providing details about the participants, number of controls, 28-day follow ups etc. These updates enable the teams to chart their progress and identify any potential issues.  

CISM team, Mozambique

  CISM team

Annual co-investigators meeting in Zimbabwe
FIEBRE team

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 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 Vilada 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 laboratory management. A range of clinical, technical, data and laboratory 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.”

Study documents

Study documents are available from this page, including the study protocol, standard operating procedures (SOPs), and text files of the data collection tools (case report forms, CRFs). You are welcome to contact us with any questions or to request documents that are not yet published.

Protocol
Version Description

v1.0  (pdf)

FIEBRE central protocol version 1.0, 1 Oct 2017 – the study protocol originally approved and implemented at study sites 
v3.0 (pdf) FIEBRE central protocol version 3.0, 31 Oct 2018 – supersedes all previous versions
v4.0 (pdf) FIEBRE central protocol version 4.0, 28 Feb 2019 – supersedes all previous versions
v4.2 (pdf) FIEBRE central protocol version 4.2, 15 Apr 2019 – supersedes all previous versions
  Social science forms
  Drug bag questionnaire data collection form (pdf)

 

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
  • Blogs
Publications List Block
The drug bag method: lessons from anthropological studies of antibiotic use in Africa and South-East Asia
Justin Dixon, Eleanor MacPherson, Salome Manyau, Susan Nayiga, Yuzana Khine Zaw, Miriam Kayendeke, Christine Nabirye, Laurie Denyer Willis, Coll de Lima Hutchison & Clare I. R. Chandler
2019
Global Health Action doi: 10.1080/16549716.2019.1639388
Current accounts of antimicrobial resistance: stabilisation, individualisation and antibiotics as infrastructure
Clare I R Chandler
2019
Palgrave Communications 5, Article number: 53 (2019)
If it's not Malaria, What is Causing the Fever?
Quique Bassat
2019
ISGlobal Health is Global Blog
How context can impact clinical trials: a multi-country qualitative case study comparison of diagnostic biomarker test interventions
Marco J. Haenssgen, Nutcha Charoenboon, Nga T. T. Do, Thomas Althaus, Yuzana Khine Zaw, Heiman F. L. Wertheim and Yoel Lubell
2019
Trials 2019 20:111
Accounting for aetiology: can regional surveillance data alongside host biomarker-guided antibiotic therapy improve treatment of febrile illness in remote settings?
Chandna A, White LJ, Pongvongsa T, Mayxay M, Newton PN, Day NPJ, Lubell Y.
2019
Wellcome Open Res. 2019 Jan 2;4:1. doi:10.12688
Harnessing alternative sources of antimicrobial resistance data to support surveillance in low-resource settings
Elizabeth A Ashley,  Nandini Shetty,  Jean Patel,  Rogier van Doorn, Direk Limmathurotsakul , Nicholas A Feasey,  Iruka N Okeke, Sharon J Peacock
2018
Journal of Antimicrobial Chemotherapy, Volume 74, Issue 3, 1 March 2019, Pages 541–546
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
Febrile illness in Asia: gaps in epidemiology, diagnosis and management for informing health policy
Shrestha P1, Roberts T, Homsana A, Myat TO, Crump JA, Lubell Y, Newton PN
2018
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Emerging Resistance to Empiric Antimicrobial Regimens for Pediatric Bloodstream Infections in Malawi (1998–2017)
Pui-Ying Iroh Tam, Patrick Musicha Kondwani Kawaza, Jenifer Cornick, Brigitte Denis, Bridget Freyne, Dean Everett, Queen Dube, Neil French, Nicholas Feasey, Robert Heyderman
2018
Clinical Infectious Diseases, Volume 69, Issue 1, 1 July 2019, Pages 61–68, doi.org/10.1093/cid/ciy834
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
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Fever Diagnostic Technology Landscape
Unitaid, World Health Organisation
2018
Unitaid Technology Landscape, 1st edition
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Crump JA, Newton PN, Baird SJ, Lubell Y.
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2017
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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
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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
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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) 

MOS-DEF logo

The Marker of Severity Diagnostics for Evaluating Fever (MOS-DEF) project is a sub-study of FIEBRE funded by Global Good. 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.

Markers of immune and endothelial activation

Biomarker Name
CRP  C-reactive protein 
PCT     procalcitonin 
Chitinase     chitinase 
Ang-1  angiopoietin-Tie-1
Ang-2  angiopoietin-Tie-2
Azu/HBP   azurocidin 1/heparin binding protein
FLT-1  fms-like tyrosine kinase-1 
sTNFR-1 soluble tumour necrosis factor receptor -1 
TREM-1 triggering receptor expressed on myeloid cells-1
TRAIL TNF-related apoptosis-inducing ligand
IL-6 interleukin-6
IL-8   interleukin-8
IL-10 interleukin-10
IP-10 interferon gamma-induced protein 10
MxA  myxovirus resistance protein A

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
Location: Zimbabwe
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, 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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