Aetiology

Worldwide, infectious diseases remain the most common cause of fever of unknown origin (FUO).[5][6][7]​​[8]​ Other causes include non-infectious inflammatory conditions (including autoimmune diseases), neoplasms and miscellaneous conditions. There is no universal FUO disease classification, although attempts are being made to agree a standardised approach.[9]

Infections

One systematic review and meta-analysis (search dates 1 January 1997 to 31 March 2021), which included 2667 cases of FUO, found that 37% had an infectious cause. Infections were more likely from the Southeastern Asia populations than from European populations. No studies were available for Africa or the Americas. Among specifically reported infectious diseases (n=832), Mycobacterium tuberculosis complex was the most common across all geographical regions (34.3%), followed by brucellosis (9.7%), endocarditis (7.5%), abscesses (7.3%), herpesvirus infections (7.2%), pneumonia (6.5%), urinary tract infections (6.5%), and enteric fever (4.8%).[6]

Non-infectious inflammatory conditions

Non-infectious inflammatory conditions as a cause of FUO have significantly increased over time, with studies from the Netherlands and Japan assessing them as the most common cause.[7][10][11]​​

Quantification of the most common non-infectious disease causes of FUO was studied in a systematic review and meta-analysis of 2667 cases of FUO, which underscored geographical variation based upon the six WHO regions.[12] Researchers reported that studies were only available for parts of Africa and the Americas. Among available data for non-infectious inflammatory conditions, 34.3% were collagen-vascular diseases, 10.2% were vasculitis syndromes, and 7.4% were non-infectious granulomatous conditions. Non-infectious inflammatory conditions were most widely reported by European studies (69.2%) compared to other regions combined (30.8%). Autoimmune disorders commonly associated with unknown fever include adult-onset Still's disease, polymyalgia rheumatica, temporal arteritis, systemic lupus erythematosus, and inflammatory bowel disorders. Participants with collagen-vascular diseases were primarily diagnosed with adult-onset Still’s disease (114 [58.5%]), systemic lupus (52 [26.7%]), and polymyalgia rheumatica (11 [5.6%]). Eastern Mediterranean cohorts had more systemic lupus cases recorded than other regions. Forty of 58 (68.9%) participants with vasculitis syndrome in this composite were diagnosed with giant-cell arteritis. The studies reviewed did not provide age-related information. For the subset of non-infectious granulomatous diseases, most (26 of 42 [61.9%]) had sarcoidosis.

Another systematic review with meta-analysis of 67 studies (16,790 cases) published between 2002 and 2021 reported Adult-onset Still’s disease (22.8%), giant cell arteritis (11.4%), and systemic lupus erythematosus (11.1%) as the most frequent causes of FUO-associated rheumatic disease. These were significantly more common in high-income countries (25.9%) compared to middle-income countries (19.5%), and were associated with increased fever duration and patients with inflammation of unknown origin.[13]

Periodic fever syndromes are autoinflammatory diseases that present with recurrent episodes of fever and systemic inflammation, without evidence of autoantibody production or infection. Examples include familial Mediterranean fever, cryopyrin-associated periodic syndrome, tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), and mevalonate kinase deficiency.[14][15]​​​ The diagnosis of periodic fever syndromes has improved through increased recognition and genetic testing; they should be considered in patients with FUO and recurrent fevers.[16][17]​​

Neoplasms

In a systematic review and meta-analysis of 2667 cases of FUO, 404 (15.1%) had an oncological-associated cause. Of these, 234 (57.9%) had a haematological malignancy. Rates were higher among studies from Europe (41.9%) and Southeast Asia (35.9%). Lymphomas accounted for the most significant number in this category (70.1%), followed by leukaemias (25.2%), multiple myeloma (3.4%), and myelodysplastic disease (1.3%).[12]

Miscellaneous conditions

Miscellaneous causes of FUO include drug-induced, thyroid disease, habitual hyperthermia, gout and pseudogout, venous thrombosis events, Kikuchi’s disease, Addison’s disease, and Dressler’s syndrome. There is geographical variation in the prevalence of some of these conditions; for example, thyroid diseases occur across all World Health Organization regions, while Kikuchi’s disease is most common across the Western Pacific and Southeast Asian regions.[12]

Undiagnosed illness

The number of cases of FUO where the cause remains undetermined has been reported to be around 20% (range 8.5% to 51.0%).[6]​​[7][12]​​ It has a very good prognosis typically resolving without significant sequelae; rates of spontaneous fever resolution in one meta-analysis were 96%.[12]

Use of this content is subject to our disclaimer