Acute febrile illness (AFI), a common reason for people seeking medical care globally, represents a spectrum of infectious disease etiologies with important variations geographically and by population. There is no standardized approach to conducting AFI etiologic investigations, limiting interpretation of data in a global context. We conducted a scoping review to characterize current AFI research methodologies, identify global research gaps, and provide methodological research standardization recommendations.


Using pre-defined terms, we searched Medline, Embase, and Global Health, for publications from January 1, 2005–December 31, 2017. Publications cited in previously published systematic reviews and an online study repository of non-malarial febrile illness etiologies were also included. We screened abstracts for publications reporting on human infectious disease, aimed at determining AFI etiology using laboratory diagnostics. One-hundred ninety publications underwent full-text review, using a standardized tool to collect data on study characteristics, methodology, and laboratory diagnostics. AFI case definitions between publications varied: use of self-reported fever as part of case definitions (28%, 53/190), fever cut-off value (38·0°C most commonly used: 45%, 85/190), and fever measurement site (axillary most commonly used: 19%, 36/190). Eighty-nine publications (47%) did not include exclusion criteria, and inclusion criteria in 13% (24/190) of publications did not include age group. No publications included study settings in Southern Africa, Micronesia & Polynesia, or Central Asia. We summarized standardized reporting practices, specific to AFI etiologic investigations that would increase inter-study comparability.


Wider implementation of standardized AFI reporting methods, with multi-pathogen disease detection, could improve comparability of study findings, knowledge of the range of AFI etiologies, and their contributions to the global AFI burden. These steps can guide resource allocation, strengthen outbreak detection and response, target prevention efforts, and improve clinical care, especially in resource-limited settings where disease control often relies on empiric treatment. PROSPERO: CRD42016035666.

Author summary

Acute febrile illness (AFI) is a common reason for people seeking medical care globally with potentially serious infectious etiologies. However, AFI has no current consensus standardized approach when considered as a syndromic case definition for public health surveillance or research, especially in global settings where AFI treatment is performed with limited diagnostic availability. Therefore, the aim of this review was to describe current methodologies in AFI research, identify gaps in research, and provide recommendations for standardization of AFI research. We screened abstracts and completed full-text reviews on publications found through an extensive search. A total of 190 publications were included in the final review, from which we collected data on study characteristics, methodology, and laboratory diagnostics. These collected data elements allowed us to identify where there were inconsistencies in reporting and investigative methods, which data elements were not regularly collected, and what laboratory testing methods were commonly used. Standardized reporting methods for AFI investigations, along with laboratory testing capacity for multiple pathogens, can improve our knowledge of the causative agents of AFI in certain regions of the world. This can help us determine where resources are needed, how to strengthen outbreak detection and response, and how to improve medical care, especially in regions with limited resources.

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Citation: Rhee C, Kharod GA, Schaad N, Furukawa NW, Vora NM, Blaney DD, et al. (2019) Global knowledge gaps in acute febrile illness etiologic investigations: A scoping review. PLoS Negl Trop Dis 13(11): e0007792. https://doi.org/10.1371/journal.pntd.0007792