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

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.