A stepwise diagnostic framework for recurrent unexplained fever in adults: an evidence-based review with focus on Latin America

Abstract

Background and methods Recurrent fever is a complex clinical presentation that poses significant diagnostic challenges, particularly when no clear etiology emerges despite extensive investigation. This integrative narrative review provides a comprehensive overview of recurrent fever and proposes a practical diagnostic flowchart focused on the most frequent etiologies, with particular emphasis on the Latin American and Brazilian contexts. Literature from MEDLINE/PubMed, LILACS, and SciELO was reviewed to summarize evidence on epidemiology, differential diagnosis, and diagnostic strategies. Results Recurrent fever may arise from infectious diseases, autoimmune or autoinflammatory disorders, malignancies, metabolic or occupational conditions, drug-induced etiologies, and factitious causes. Infections, notably tuberculosis, malaria, leishmaniasis, and endocarditis, remain leading contributors in developing countries. Non-infectious causes such as rheumatologic conditions, neoplasms, and inborn errors of immunity must also be considered, especially in persistent or unexplained cases. A structured, tiered approach to diagnosis is recommended, beginning with basic laboratory and imaging studies, progressing to targeted invasive procedures and advanced modalities such as 18F-FDG PET/CT, and, when appropriate, genomic sequencing. The flowchart proposed in this review emphasizes clinical history, frequent reassessment, and the judicious use of diagnostic resources to balance cost-effectiveness and diagnostic yield. Moreover, distinguishing between inflammatory and non-inflammatory patterns, as well as identifying the newly described Syndrome of Undifferentiated Recurrent Fever (SURF), may guide further evaluation. Ultimately, recurrent fever requires a systematic and multidisciplinary approach. Incorporating epidemiological context and advances in molecular and imaging technologies may improve diagnostic accuracy and patient outcomes.