Severe febrile illness without a known source (SFWS) represents a significant medical burden in hospitals run by Doctors Without Borders/ Médecins Sans Frontières (MSF). Some 50 percent of patients in low-income countries are admitted with a fever. Our clinicians currently lack the tools to properly diagnose the cause of these febrile illnesses, which have a much higher mortality rate than other causes of admissions. The inability to distinguish the cause of infections can lead to the over-use of antibiotics, or use of the wrong antibiotics, contributing to the growing problem of antibiotic resistance.
The Febrile Illness Diagnostic Program, hosted by MSF-USA on behalf of our operational center in Paris (OCP) and in collaboration with the operational center in Barcelona (OCBA), is exploring the potential of a new diagnostic tool that could transform the way clinicians treat patients with severe febrile illness. This tool is called the MAPDx: a multiplex and multi-analyte diagnostic platform designed to detect a broad range of pathogens. MAPDx could also dramatically expand MSF’s diagnostic capabilities beyond febrile illness.
MSF and FIND, a global nonprofit organization that works to advance innovative diagnostics, have partnered with the World Health Organization to develop a consensus target product profile (TPP) for MAPDx. MSF is now considering whether to support the creation of a research and development program to make the MAPDx a reality and bring it to the field.
Fever is one of the most common reasons for admission to hospitals in low-resource settings. Among the millions of patients MSF sees each year, the problem of severe febrile illness without a known source (SFWS) is common. A 2018 retrospective chart review conducted in MSF hospitals in Monrovia, Liberia, and Borno, Nigeria, found that SFWS represented 9.7 percent of admissions in Liberia and 13.5 percent of admissions in Nigeria. This was, on average, the fourth most significant cause of admission for both hospitals after malaria (50.0 percent), lower respiratory tract infection (18.5 percent), and non-bloody diarrhea (12.2 percent). The same chart review compared mortality rates among patients who fit the definition of SFWS against the rate among those who did not. For SFWS patients, the mortality rate was more than double: 17.5 percent versus 6.5 percent in Liberia and 16.7 percent versus 7.1 percent in Nigeria.
In a separate analysis conducted by the Febrile Illness Diagnostic Program (FIDP), it was estimated that in 2014 a median of 16.2 million hospitalizations occurred due to severe febrile illness in sub-Saharan Africa (This number included SFWS and other causes of severe febrile illness).
The inability to distinguish the cause of infections can lead to the over-use of antibiotics, or use of the wrong antibiotics, contributing to the growing problem of antibiotic resistance.
To better address this medical need, MSF-USA, on behalf of OCP and in collaboration with OCBA, implemented a Febrile Illness Diagnostic Program in order to:
- Improve MSF’s capacity to diagnose the cause of SFWS and care for affected patients;
- Determine whether MSF should invest in a program to create a new diagnostic test to determine the pathogenic cause of SFWS for use in MSF settings and beyond; and
- Transform MSF’s diagnostic capacity more broadly.
Multiplex, Multi-analyte Platform Diagnostic
To respond to medical needs and fill gaps in current diagnostic technologies, MSF has been exploring the feasibility of working with partners to develop a novel multiplex, multi-analyte platform diagnostic (MAPDx). The first clinical target for the MAPDx is a test cartridge for severe febrile illness.
As conceived, the MAPDx could simultaneously detect multiple pathogens and analyte types (i.e., nucleic acids, antigens, antibodies, or other serological molecules) on a single platform using a single sample. Having multiplex capability is important for syndromic management of patients in cases where there are many potential causes for the given symptoms. The multi-analyte capability is important because different pathogens require different detection methods, and sometimes more than one. Given the envisioned flexibility of the platform, it would have many applications beyond febrile illness.
An additional goal is that the MAPDx would be developed using a semi-open business model, meaning that any qualified developer could obtain the assay design requirements from the instrument manufacturer and use them to manufacture assays to run on the platform. This would enable a much broader menu of assays that can be customized to fit MSF needs in diverse projects around the world.
While the initial focus is on individual clinical care at the referral level for diagnosing SFWS, the envisioned design of the platform would mean that test cartridges for many other conditions would be possible, including for other global health imperatives such as HIV, tuberculosis, malaria, and prenatal health.
A review of existing initiatives shows that none align with MSF’s design vision, but that technology is moving in a direction to make our program’s goal achievable.
This initial phase of work, undertaken in collaboration with FIND and lasting until March 2019, lays out critical information about how to strengthen the treatment and diagnosis of severe febrile illness in MSF settings. The reporting and analysis conducted over nearly four years are intended to enable a decision on whether or not MSF should support an R&D program to create MAPDx. The outcomes for the program are:
- Improved data on the scope of SFWS in MSF settings;
- A diagnostic algorithm for managing SFWS at hospital level;
- Clear understanding of tools that may improve diagnosis of the cause of febrile illnesses in the short-, medium-, and long-term, including how the MAPDx could fit in;
- A target product profile for MAPDx to guide the diagnostic R&D community; and
- Evaluation of the feasibility of a program to develop the MAPDx.
The core Febrile Illness Diagnostic Program team—working in collaboration with FIND—is carrying out six work streams supported by the executive of MSF-USA and the OCP medical department, as well as an advisory committee representing all OCs, the Access Campaign, Epicentre, and DNDi. The work streams are:
- Development of WHO-backed consensus TPPs for the MAPDx, and a TPP for a first cartridge for SFWS;
- Estimation of the scope of severe febrile illness in MSF settings and beyond and a clinician survey on management of febrile illness;
- A diagnostic algorithm to guide clinicians in diagnosing the cause of SFWS;
- Prevalence studies on pediatric patients in Uganda and Mali to better understand the prevalence of pathogens of interest that cause SFWS;
- Business case and IP strategy development to further establish the feasibility of developing MAPDx and identification of diagnostic companies that could undertake development; and
- Expanded landscape review of existing and pipeline diagnostic technologies relevant to SFWS to identify technologies applicable to MAPDx and to avoid duplication of existing efforts.
Proposal and Deliverables from Work Streams
A report synthesizing the analysis of all 32 reports generated by the MSF Febrile Illness Diagnostic Program and FIND during this phase is currently being evaluated. The report proposes a path forward to work with FIND and diagnostic companies to create the MAPDx.
To find out more, contact the Febrile Illness Diagnostic Program manager, Ethan Guillen, at email@example.com