No standardized diagnostic strategy could be determined. The diagnostic process should be guided by the potential diagnostic clues (PDCs) emerging from the history, physical examination and baseline tests. A standardized flow chart can be applied only in absence of PDCs or when the PDCs are contradictory.Nuclear medicine techniques are a valuable aid in the search for the origin of FUO due to bacterial infections or in the absence of PDCs.

Background The differential diagnosis of Fever of Unknown Origin (FUO) is very extensive, and includes infectious diseases (ID), neoplasms and noninfectious inflammatory diseases (NIID). Many FUO remain undiagnosed. Factors influencing the final diagnosis of FUO are unclear. Methods To identify factors associated with FUO diagnostic categories, we performed a systematic review of classical FUO case-series published in 2005–2015 and including patients from 2000. Moreover, to explore changing over time, we compared these case-series with those published in 1995–2004. Results Eighteen case-series, including 3164 patients, were included. ID were diagnosed in 37.8% of patients, NIID in 20.9%, and neoplasm in 11.6%, FUO were undiagnosed in 23.2%. NIIDs significantly increased over time. An association exists between study country income level and ID (increasing when the income decreases) and undiagnosed FUO (increasing when the income increases); even if not significant, the use of a pre-defined Minimal Diagnostic Work-up to qualify a fever as FUO seems to correlate with a lower prevalence of infections and a higher prevalence of undiagnosed FUO. The multivariate regression analysis shows significant association between geographic area, with ID being more frequent in Asia and Europe having the higher prevalence of undiagnosed FUO. Significant associations were found with model of study and FUO defining criteria, also. Conclusions Despite advances in diagnostics, FUO still remains a challenge, with ID still representing the first cause. The main factors influencing the diagnostic categories are the income and the geographic position of the study country.

Adenosine deaminase in the peripheral lymphocytes (L-ADA) was determined in 27 patients with typhoid fever and in 15 normal controls. Increased values of enzymatic activity were found in the typhoid fever patients compared with the controls. The increase was prolonged and not correlated to treatment. L-ADA levels could be related to the immune response.