Since the discovery of penicillin by Alexander Fleming nearly a century ago, antibiotics have transformed healthcare. Recollections are waning that seemingly innocuous diseases, such as strep throat, were once fatal. But antibiotics are falling victim to their own success. Today’s widespread use of these wonder drugs – not just in human health but also in animal health and agriculture – is allowing bacteria to learn how to develop resistance to these drugs, and antimicrobial resistance (AMR) is now recognized globally as a public health emergency.
Overuse, and misuse, of antibiotics is a big part of the problem. But with around 100 million children presenting to health facilities with non-malarial fever every year in Africa alone, health professionals are faced with a dilemma. Most febrile illnesses have non-specific signs and symptoms. In the absence of diagnostic tools to establish the cause of the fever, a “just in case” antibiotic prescription is often the only available course of action to prevent a child from possibly dying. Even if recent data show that in South East Asia, viruses like dengue or chikungunya are the most likely culprits, “most likely” is not good enough to put a child’s life at risk, despite the AMR risks.
Biomarker research could unlock a potential new approach. C-reactive protein (CRP), a marker associated with bacterial infection, is already routinely used in high-income countries to guide treatment decisions. A CRP test combined with a rapid diagnostic for malaria is currently in development and holds some promise for low-resource settings. However, while repurposing this technology for low-income settings is an important step forward, further innovation remains critical to improve on this imperfect and relatively unspecific marker.
In 2016, a consortium of global health and diagnostics experts including the World Health Organization (WHO), ReAct, Médecins Sans Frontières (MSF) Access Campaign and FIND developed a target product profile (TPP) for an assay that can distinguish bacterial from non-bacterial infections, in low-resource settings, to provide actionable, evidence-based treatment guidance with the potential of reducing unnecessary prescription of antibiotics.
To help realize the potential of this approach, FIND has established several tools to enable and accelerate development of new innovations that could meet the criteria of the TPP. A dedicated resource has been set up to provide developers with a comprehensive overview of available biomarker candidates: Bm2Dx is a freely accessible database that provides wide-ranging biomarker information, as well as search and analysis tools. FIND also manages a specimen bank of well-characterized disease samples – including fever – to support commercial and academic researchers in the development and evaluation of new and existing diagnostic tools. Fever samples undergo an extensive bacterial versus non-bacterial classification process.
At the American Society for Tropical Medicine and Hygiene (ASTMH) meeting this week, we are presenting initial data from a new study, one of the largest ever conducted in this area, designed to evaluate candidate biomarkers in low-resource settings. Nearly 2,000 patients are being enrolled at sites in Brazil, Malawi and Gabon . The countries have been chosen to span very different epidemiological contexts with diverse circulating pathogen profiles. The same protocol and analysis is being employed at all sites, to enable comparison between the different countries and settings. Through this stringent validation in settings of intended use, the Biomarkers For Fever Diagnostics (BFF-Dx) study will generate transparent data and provide critical new information that could transform development of urgently needed fever diagnostics. This can inform prescribing decisions that will improve patient care and help tackle AMR.
Yet despite the clear need and opportunity, the research and development pipeline remains relatively bare. There has been almost no new entrants in recent years. Some existing biomarker tests targeted to high-income settings – including CRP – are now being explored in low-resource settings. But development efforts on high-performing markers for the different bacterial profiles found in the Global South has been largely been left out.
While host biomarker research to support fever management is indeed challenging, we cannot afford to leave any stone unturned. With AMR cemented as a public health priority, there is political support at both national and international levels for potential solutions.
The need is there. The resources are there. The political will is there. Where are the developers?
About the authors :
Sabine Dittrich , works at the Foundation for Innovative New Diagnostics (FIND), Geneva, Switzerland
Selidji Maxime Agnandji works at the Centre de Recherches Médicales de Lambaréné (CERMEL), Albert Schweitzer Hospital, Lambaréné, Gabon
Steffen Geis works at the Malawi Epidemiology and Intervention Research Unit (MEIRU), Karonga, Malawi
Andre Machado Siqueira works at the Instituto Nacional de Infectologia Evandro Chagas – Fiocruz, Rio de Janeiro, Brazil
Competing Interests:
We have read the BMJ policy on declaration of interests and declare that we have no relevant conflicts of interests to declare.