Unexplained Febrile Syndromes in Sub-Saharan Africa: Etiological Diversity, Diagnostic Challenges and Emerging Diagnostic Approaches—A Narrative Review

Unexplained febrile syndromes represent a major diagnostic and public health challenge in Sub-Saharan Africa. Although malaria remains an important cause of fever, an increasing proportion of febrile episodes is attributable to nonmalarial etiologies, encompassing a wide range of bacterial, viral, parasitic, and fungal infections, as well as noninfectious causes. Their etiological characterization remains limited by the low specificity of clinical manifestations, the heterogeneity of definitions and diagnostic algorithms, and insufficient laboratory capacity. Microscopy, rapid diagnostic tests, cultures, and serology remain essential in resource-limited settings, but their targeted nature and variable performance may lead to diagnostic dead ends. Emerging approaches, particularly multiplex PCR, next-generation sequencing, and clinical metagenomics, offer new opportunities to broaden the diagnostic spectrum, identify neglected or emerging pathogens, and strengthen surveillance. However, their integration requires strengthening laboratory networks, quality systems, and human resources, as well as evaluating their relevance and cost-effectiveness. An integrated approach based on the “One Health” concept appears essential to improve the diagnosis and surveillance of febrile illnesses in Sub-Saharan Africa.