Fever of Unknown Origin
Written 6th August 2020 - Last Update 24th August 2026
Fever of unknown origin
FUO = temperature ≥38.3 °C that persists without a diagnosis despite appropriate evaluation, and isn’t explained by a transient self-limited illness or by clear localising features/abnormal common tests. For fever after travel, see Illness in returned traveller.
Categories
- Classic — fever >3 weeks, undiagnosed after 3 days of inpatient work-up or ≥3 outpatient visits.
- Healthcare-associated — in an inpatient, no infection present/incubating on admission, undiagnosed after 3 days.
- Immune-deficient (neutropenic) — undiagnosed after 3 days (including negative cultures at 48 h).
- Travel-associated — recognising a life-threatening or transmissible travel-related infection should be the priority; a confirmed-HIV patient’s fever is now worked up under the immunodeficiency-related category above rather than as its own class (see GUIDELINE-UPDATE below).
Causes
- Infection (commonest) — abscesses, endocarditis, TB, osteomyelitis; in HIV, opportunistic infections (TB/atypical mycobacteria, disseminated fungi, CMV).
- Connective tissue / inflammatory — SLE, RA, giant cell arteritis, vasculitis, adult-onset Still disease.
- Neoplastic — lymphoma, leukaemia, renal cell and hepatocellular carcinoma, metastases.
- Miscellaneous — drug fever, VTE/recurrent PE, sarcoidosis, IBD, factitious fever. ~10% of adults remain undiagnosed.
Consider locally-relevant “great imitators” too: brucellosis has earned its place alongside syphilis and tuberculosis as one of the “great imitators” and causes of pyrexia of unknown origin — it is re-emerging in Australia through feral pig hunting, alongside the more familiar travel/ unpasteurised-dairy exposure route, and its non-specific symptoms (relapsing fever, sweats, arthralgia, myalgia) readily mimic TB, toxoplasmosis, infectious mononucleosis or SLE.
Assessment
- History — fever pattern (usually unhelpful, but tertian/quartan suggests malaria in at-risk patients); B-symptoms (weight loss, night sweats); connective-tissue and GI symptoms; PMH (cancer, TB, IBD, valve/device); exposure/social history (injecting drug use, sexual history, TB contacts, travel, animal/tick vectors); family history (e.g. familial Mediterranean fever).
- Examination — skin (endocarditis stigmata: Osler nodes, Janeway lesions, splinter haemorrhages; SLE malar rash), lymphadenopathy pattern, thorough palpation (spine/bones/joints/abdomen/thyroid), cardiac murmurs/rubs, dental percussion, and rectal/pelvic exam.
- Red flags: immunocompromise, a heart murmur, indwelling devices, recent travel to endemic areas.
Investigations
FBC, ESR/CRP, LFTs, serial blood cultures (before antimicrobials), HIV testing, TB test (IGRA/tuberculin), ANA/RF, urinalysis and culture, CXR, targeted CT/MRI, transthoracic echocardiography, venous Doppler, and tissue biopsy (histopathology/culture/PCR). PET/CT is increasingly useful when first-line tests don’t localise a source.
Management
There’s no single standard FUO management protocol given the range of possible causes — the priority is to investigate and narrow the differential, not to treat empirically. Empiric antibiotics are not indicated unless the patient is neutropenic, since they can delay diagnosis of an occult infection; empiric glucocorticoids are not indicated unless there’s strong clinical suspicion of a specific rheumatological diagnosis. Once a diagnosis is made, treat it specifically.
Exceptions where empiric treatment is justified despite an inconclusive work-up: culture-negative endocarditis, cryptic disseminated TB (or other granulomatous infection), and suspected giant cell (temporal) arteritis with threatened vision loss — treat the last of these with high-dose (intravenous if severe or ocular symptoms are present) glucocorticoids without waiting for biopsy confirmation. Temporal artery biopsy should still be arranged in a patient over 60 with a markedly elevated ESR and features suggestive of giant cell arteritis, and lymph node biopsy if lymphadenopathy is found on examination.
Nuclear medicine imaging — traditionally reserved for cases still undiagnosed after a full initial evaluation — is increasingly used earlier in the work-up: FDG-PET/CT is highly sensitive (though nonspecific) for localising infectious, inflammatory or neoplastic processes, and can guide a subsequent targeted biopsy even when it can’t itself confirm a diagnosis. Labelled-leukocyte studies are an alternative where PET isn’t available, though with a lower diagnostic yield.
Most FUO resolves spontaneously over weeks to months even without a diagnosis being reached, and prognosis in that undiagnosed group is generally good. NSAIDs can be used for symptomatic relief in a stable patient without a diagnosis while investigations continue.