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

Abstract

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 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). 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; 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. Conclusions. 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.