A scoping review of fever of unknown origin with normal serum C-reactive protein

The differential diagnosis of fever of unknown origin (FUO) resembles that of inflammation of unknown origin (IUO), but the concept and differential diagnosis of FUO with no inflammatory laboratory evidence (FUO-NIL) are unknown. The aim was to propose the concept of FUO-NIL and explore its differential diagnosis.

The present study is a scoping review of FUO-NIL, defined as FUO with normal serum C-reactive protein (CRP). The PubMed, Embase, CENTRAL, Web of Science, and Google Scholar databases were searched for relevant information. A study was considered eligible for enrolment if the final diagnosis was definitive and the CRP value was clearly noted as normal in each case. The data extracted included the patients' clinical information, final diagnosis, diagnostic tests performed, treatments, and outcomes.

The full text of 342 of 3,084 articles were reviewed, and 17 articles met the inclusion criteria. The review identified 19 cases that were eligible for quantitative analysis. The disease categories were infection (n=10, 52.6 %), malignancy (n=3, 15.8 %), non-infectious, inflammatory disease (n=4, 21.1 %), and miscellaneous (n=2, 10.5 %). A more specific differential diagnosis included intracellular fungal infection, tuberculosis, malignancy, systemic lupus erythematosus, granulomatous diseases, Fabry disease, hemophagocytic lymphohistiocytosis, and functional hyperthermia. FUO-NIL may have a unique differential diagnosis and have a different etiology from that of inflammatory FUO. In addition to the standard diagnostic work-up for FUO, tailored diagnostic strategies, including checking for a history of animal contact, the presence of hypohidrosis, and psychosocial stressors may be warranted in cases of FUO-NIL.