Background: Criteria classifying fever of unknown origin (FUO) patients remains subject to discrepancies. A minimal standardized set of investigative tests serves as the foundation for the qualitative criteria, whereas quantitative incorporates the length of evaluation (7 or 3 days). A systematic review of studies would help physicians anticipate the frequency of illness types that could influence management.

Methods: Prospective studies published in Medline (PubMed), Embase, Scopus, and Web of Science databases from January 1, 1997 to July 31, 2022, were included. A meta-analysis estimated associated pooled proportions between these criteria and diagnostic outcomes adjusted to the International Classification of Diseases, 10th edition (ICD-10) definitions.

Results: Five qualitative studies corresponded to an increase of 15.3% (95% CI: 2.3%-28.3%, P = .021) in undiagnosed FUO proportions compared to eleven quantitative studies. Quantitative studies had 19.7% (95% CI: 6.0%-33.4%, P = .005) more in adjusted infectious disease proportions than qualitative studies. No significant differences in proportions between FUO defining criteria were noted for adjusted noninfectious inflammatory disorders (P = .318), oncology (P = .901), non-inflammatory miscellaneous disorders (P = .321), diagnostic evaluation process, gross national income (GNI), or World Health Organization (WHO) geographic region.

Conclusions: Use of either qualitative or quantitative FUO criteria was associated with a statistically significant risk of over- or under-estimating infectious diseases and undiagnosed illnesses when using an ICD-10 adjusted FUO five-category system. Clinicians should anticipate differences depending on which criteria are used. While further research is warranted, qualitative criteria provide the best framework for study comparisons.