Elucidating Infectious Causes of Fevers of Unknown Origin: A Laboratory-Based Observational Study in Patients With Suspected Ebola, Guinea, 2014
Background The etiology of fever of unknown origin (FUO) in sub-Saharan Africa often remains unexplained.  Methods We performed a retrospective laboratory-based observational study of 550 Guinean patients with FUO who tested 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).  Results 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, and 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 14 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 with fever (74.7%), asthenia (67.7%), emesis (38.2%), diarrhea (28.3%), and hemorrhage (11.8%), without clear etiology associations.  Conclusions An exhaustive laboratory investigation elucidated infectious causes of FUO in 52.3% of patients. Strengthening laboratory capacities in sub-Saharan Africa is essential for patient care, outbreak response, and regionally appropriate diagnostics.  Keywords Africa; bacteremia; coinfection; diagnosis; Ebola virus disease; fever of unknown origin; malaria; metatranscriptomics; PCR; serology.