Elucidating Infectious Causes of Fever of Unknown Origin: A Laboratory-Based Observational Study of Patients with Suspected Ebola Virus Disease, Guinea, 2014

• Published in: The Journal of infectious diseases Vol. 232; no. 1; pp. 101 - 112
• Main Authors: Postigo-Hidalgo, Ignacio, Magassouba, N’Faly, Krüger, Nadine, Guilavogui, Marie Louise, Kruger, Detlev H, Klempa, Boris, Drexler, Jan Felix
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 15.07.2025
• Subjects: Adolescent; Adult; Antibiotics; Asthenia; Child; Child, Preschool; Crimean hemorrhagic fever; Diarrhea; Ebola virus; Ebolavirus; Ebolavirus - genetics; Ebolavirus - isolation & purification; Etiology; Female; Fever; Fever of Unknown Origin - epidemiology; Fever of Unknown Origin - etiology; Fever of Unknown Origin - microbiology; Fever of Unknown Origin - virology; Guinea - epidemiology; Hemorrhagic Fever, Ebola - complications; Hemorrhagic Fever, Ebola - diagnosis; Hemorrhagic Fever, Ebola - epidemiology; Hemorrhagic Fever, Ebola - virology; High-Throughput Nucleotide Sequencing; Humans; Immunofluorescence; Immunoglobulin M; Infant; Laboratories; Lassa fever; Male; Middle Aged; Next-generation sequencing; Observational studies; Pathogens; Patients; Phylogeny; Polymerase chain reaction; Quality control; Retrospective Studies; Reverse transcription; Sepsis; Tropical diseases; Viruses; Vomiting; Yellow fever; Young Adult; Guinea; Africa; Coinfection; Diagnosis; Malaria; Fever of unknown origin; Bacteremia
• ISSN: 0022-1899; 1537-6613; 1537-6613
• DOI: 10.1093/infdis/jiae637

The etiology of fever of unknown origin (FUO) in sub-Saharan Africa often remains unexplained. We performed a retrospective laboratory-based observational study of 550 Guinean patients with FUO testing negative for Ebola virus from March to December 2014. Blood-borne pathogens were diagnosed by polymerase chain reaction (PCR) or reverse transcription-PCR (RT-PCR), serologic tests, and targeted and unbiased high-throughput sequencing (HTS). In 275 of 550 individuals, we found evidence of ≥1 pathogen by molecular methods. We identified Plasmodium in 35.6% of patients via PCR, with P falciparum constituting 96.4% of these cases. Pathogenic bacteria, including Salmonella and Klebsiella, were detected in 18.4% of patients through PCR and HTS. Resistance determinants against first-line antibiotics were found in 26.9% of pooled sera by HTS. Yellow fever, Lassa, and Ebola viruses were detected in 5.8% of patients by RT-PCR; HTS-guided RT-PCR confirmed Orungo virus infection in 1 patient. Phylogenetic analyses revealed that the viral genomes matched the available genomic data in terms of location and time. Indirect immunofluorescence assays revealed immunoglobulin M antibodies against yellow fever, Ebola, dengue, West Nile, and Crimean Congo hemorrhagic fever viruses in 11 of 100 patients who were PCR or RT-PCR negative. One in 5 patients who were infected presented coinfections, predominantly malaria associated with sepsis-causing bacteria, in adults (12.1%) and children (12.5%), whereas viral coinfections were rare. Patients presented fever (74.7%), asthenia (67.7%), emesis (38.2%), diarrhea (28.3%), and hemorrhage (11.8%), without clear etiology associations. An exhaustive laboratory investigation elucidated infectious causes of FUO in 52.3% of patients. Quality control and strengthening laboratory capacities in sub-Saharan Africa are essential for patient care, outbreak response, and regionally appropriate diagnostics.