The team at Centro de Investigação em Saúde de Manhiça (CISM) in Mozambique have been operational for a year. CISM began enrolling adult patients at Manhiça Health Research Centre on 13 March 2019 after paediatric recruitment started in 23 November 2018. They reached their 1000th patient in November 2019.

Recruitment started at a new site, Hospital Geral José Macamo, Maputo, on 28 November 2019. This has helped boost inpatient numbers considerably and improved the patients’ care with the performance of blood culture, urine culture and antibiotic susceptibility testing. Latest data from end of February shows 1406 patients enrolled of which 916 are outpatients and 490 inpatients. More children than adults have been enrolled. 

The team has faced several recruitment challenges during the study. Over the years, inpatient numbers have dropped at Manhiça District Hospital and there has been overlap with other studies making inpatient recruitment particularly difficult. 

Day 28 follow up has been challenging  with a high rate of refusals and some loss to follow up due to migration, accessibility and local perception of loss of blood.

Throughout the study, the team has received positive feedback from both patients and the hospital. FIEBRE has contributed to the clinical diagnostic capacity at these hospitals through access to rapid diagnostic tests and laboratory cultures. This has helped both clinicians and patients, enabling clinicians to use the information to make an accurate diagnosis and therefore provide the right treatment.

The third FIEBRE Co-investigators meeting, hosted by LOMWRU, took place in Vientiane, Laos from 11-14 February 2020.

Over 45 members of the partner organisations involved in FIEBRE attended the meeting including London School of Hygiene & Tropical Medicine, Barcelona Institute for Global Health (ISGlobal), Biomedical Research and Training Institute (BRTI), Centro de Investigacao em Saude de Manhica, Liverpool School of Tropical Medicine, Malawi-Liverpool Wellcome Trust Research Programme, Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford, Bangladesh Institute of Tropical & Infectious Diseases and Chattogram Medical College Hospital.

Researchers from the Aga Khan University also joined the meeting to learn more about the possibility of setting up a similar study in Karachi, Pakistan.

The event was attended by representatives from all aspects of the study - data, clinical, laboratory, microbiology and social science. There was a packed agenda covering updates on:

• Country sites  -  personnel, number of patients and controls recruited, logistical recruitment challenges
• Sharing solutions to operational challenges
• Laboratory activities
• Reference laboratories – status on sample shipment
• Microbiology data and early analysis
• Quantitative data analysis plan
• Social science activities
• Complementary and associated studies
• Dissemination of results and engagement
• Publications, follow-on studies and future plans 
• Potential new sites

The visit included a tour of the laboratory at Mahosot Hospital and the recruitment site Vientiane Provincial Hospital illustrating how the study operates from the initial recruitment of patients through data input to the samples being tested at the laboratory.

The meeting was very productive enabling all participants to share ideas and benefit from learning about the experiences of partners across sites and disciplines.

Members of the team and the DfID technical representative were also able to meet with the British Ambassador to explain the study.

A series of videos is being recorded of team members. These will give an insight into various different aspects of the study, from the hub at the London School of Hygiene & Tropical Medicine where FIEBRE is co-ordinated to the teams in Laos, Malawi, Mozambique and Zimbabwe who are enrolling the patients, taking samples and collecting the data.

The first video is with Dr Katharina Kranzer, the Principal Investigator in Zimbabwe, who explains how FIEBRE operates with BRTI in Harare. 

The LOMWRU team started enrolling patients on 9 October 2018 at Vientiane Provincial Hospital “Maria Teresa hospital” 60 km from Vientiane. The team recruited its 1000^th patient in early September.

Latest data from early October show 1165 patients enrolled of which 669 are inpatients and 495 outpatients.

The team comprises three doctors, two who are responsible for recruiting in- and outpatients, and one for control recruitment. There’s one laboratory technician and one person concentrating on 28-day follow-up.

The team has faced many challenges since the start due in part to the weather. Patients present with fever relating to the season. Recruitment increased during the rainy season (May to October) despite only having three doctors during a dengue fever outbreak. The enrolment rate has sped up since recruitment started 24 hours a day/7 days a week with the help of a local assistant doctor. Another challenge for the team is handling children while taking blood from them. Parents are often not willing to give consent.

Day 28 follow up is quite successful at about 80% and varies depending on the weather. Reasons for refusal include feeling much better so there's no desire for further blood tests; moving (work or life -related); geography and distance; and inability to leave work.

Community control recruitment can be like an adventure, as the countryside is very diverse and the distances so far. Some trips can take up to two hours each way. None of the trips are easy and can even involve transporting the vehicle and equipment by boat across a river.

Throughout the study, the team has always received positive feedback from both patients and the hospital. FIEBRE has been able to contribute to the clinical diagnostic capacity of infectious diseases locally, as blood culture and other tests are not available in the hospital.

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
  (Tuesday 17 September, Rm 1a, 14.00 h) 
• 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
  (Thursday 19 September, Rm 1a, 15.00 h)

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.
 

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.

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:

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. 

Meeting with FIEBRE participants and village elder

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

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 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.   

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.