Multicountry surveillance study of acute febrile disease of unknown cause in sub-Saharan Africa

Abstract

BACKGROUND : Acute Febrile Disease of Unknown Cause (AFDUC) remains a major diagnostic and clinical challenge in sub-Saharan Africa (SSA), where malaria dominates while other aetiologies are under-recognised. The African Network for Improved Diagnostics, Epidemiology and Management of common Infectious Agents aimed to enhance understanding of the epidemiology of AFDUC in SSA through clinical and laboratory-based surveillance. METHODS : A multicentre prospective sentinel surveillance case-control study was conducted across urban and rural sites in Côte d’Ivoire (CI), Burkina Faso (BF) and South Africa (SA). We enrolled 6100 AFDUC cases and 1455 healthy controls between 2018 and 2022 across all study sites. Standardised clinical, laboratory and follow-up data were collected. Diagnostics included biomolecular multiplex PCR, serology and blood culture. Associations between pathogens and AFDUC were assessed using adjusted odds ratios. RESULTS : Plasmodium falciparum remained the leading pathogen in BF and CI, and EBV was the most frequent viral detection (up to 23% in SA). HBV prevalence matched WHO estimates, while DENV and CHIKV IgM seropositivity reached 20–22% in BF and CI, with marked regional and rural-urban differences. Blood cultures had low positivity (5.4%), with Staphylococcus aureus and Salmonella spp predominating. Mortality was highest in BF (22%), particularly in adults ≥45 years, and largely attributed to unresolved febrile illness. Across sites, HIV infection, comorbidities and neurological symptoms were linked to poor outcomes. Mortality patterns mirrored health system disparities, with lowest physician density and health spending in BF. Despite broad testing, no pathogen was detected in 65% of cases. CONCLUSIONS : Our results highlight the need for improved diagnostics of common and zoonotic pathogens in SSA and provide insights into febrile disease aetiologies. Strengthened laboratory surveillance, improved case management and targeted vector control are critical to reduce the burden of febrile illness.