Fever of unknown origin (FUO)

Fever that won't go away — investigating prolonged fever in AU general practice

By Dr HB Lo, FACRRM 8 min read

Fever of unknown origin (FUO) is defined as a temperature of 38 °C or above on multiple occasions over three or more weeks, with no diagnosis found after an appropriate initial workup. It can signal serious underlying conditions — infections like tuberculosis, malignancy like lymphoma, or inflammatory diseases like vasculitis.

In Australia, the GP's role is to take a careful history (travel, animal, and occupational exposures), examine systematically, and order structured investigations. PET-CT is the preferred next imaging step when first-line workup is unrevealing. About 20–30% of cases resolve without a confirmed cause.

What is a fever of unknown origin?

Most fevers last a few days, have an obvious cause — a respiratory tract infection, a urinary tract infection, the flu — and resolve without extensive investigation. Fever of unknown origin (FUO) is the formal medical term for a different situation: fever of 38 °C or above, documented on multiple occasions over at least three weeks, with no diagnosis found after an appropriate initial workup.

The definition originated with Durack and Street in 1991 (Curr Clin Top Infect Dis) and has been updated since to reflect modern diagnostic tools. Modern guidelines often use a two-week threshold rather than three, and 38.0 °C rather than 38.3 °C. What the definition is trying to capture is: a fever that persists long enough, and resists easy explanation, that a structured and systematic diagnostic process is required.

This is not a common presentation, but it is an important one — because the causes that don’t reveal themselves early are sometimes the ones that matter most.

A. Core clinical — the AU general-practice framework

The four classical subclasses

The Durack-Street framework (Curr Clin Top Infect Dis 1991) divides FUO into four subclasses that carry different differentials and workup priorities:

  1. Classic FUO — community-acquired prolonged fever; the broadest differential. Most GP presentations.
  2. Nosocomial FUO — fever beginning more than 48 hours after hospital admission, with no fever at admission. The differential includes hospital-acquired infections, pulmonary embolism, and drug fever.
  3. Neutropenic FUO — absolute neutrophil count below 500 per microlitre with fever. This is an oncological or haematological emergency, not a community general practice scenario.
  4. HIV-associated FUO — in a person with known HIV infection, fever persisting more than four weeks outpatient or more than three days inpatient without diagnosis.

What causes FUO?

The three largest categories, from pooled modern series (Wright Open Forum Infect Dis 2020; AAFP 2022):

Infections (30–40%): Tuberculosis is the most common single infection. Infective endocarditis (heart-valve infection) is critical not to miss — especially in intravenous drug users, those with prosthetic valves, or those with prior valve disease. Intra-abdominal and pelvic abscesses; osteomyelitis; dental abscess; chronic sinusitis. Viral causes include Epstein-Barr virus (EBV), cytomegalovirus (CMV), HIV seroconversion, and viral hepatitis. Zoonoses are particularly relevant in Australia: Q fever from cattle, sheep, and kangaroos; leptospirosis from water contaminated by animal urine; brucellosis from unpasteurised dairy and livestock; melioidosis in tropical northern Australia from soil and water; scrub typhus from mite bites in some regions.

Malignancy (20–30%): Lymphoma accounts for approximately half of malignancy-related FUO. Leukaemia, renal cell carcinoma, hepatocellular carcinoma, and atrial myxoma are also described. Malignancy-related fever is typically driven by cytokine release and tumour necrosis.

Non-infectious inflammatory conditions (approximately 20%): Adult-onset Still’s disease is a systemic inflammatory condition of young to middle-aged adults presenting with quotidian (daily-spiking) fever, evanescent salmon-coloured rash, arthritis, and elevated ferritin. Large-vessel vasculitis — giant cell arteritis and Takayasu arteritis — commonly presents with fever, elevated inflammatory markers, and can precede the classic vascular or visual features by months. Polymyalgia rheumatica, polyarteritis nodosa, sarcoidosis, inflammatory bowel disease, and systemic lupus erythematosus are other important considerations.

Drug fever (3–5%): A pure hypersensitivity response to medication — often with normal white cell count, elevated eosinophils, and prompt resolution on drug withdrawal. High-risk drugs include sulfonamide and beta-lactam antibiotics, nitrofurantoin, antiepileptics (phenytoin, carbamazepine), allopurinol, antithyroid drugs, and certain antihypertensives. A medication reconciliation that includes all medicines started in the past three months — including over-the-counter and herbal preparations — is essential.

Idiopathic / undiagnosed (20–30%): Despite thorough investigation, a quarter to a third of FUO cases receive no definitive diagnosis. Most of these resolve spontaneously and without serious consequence — which, while unsatisfying diagnostically, is generally reassuring.

B. The diagnostic workup

History — where the diagnosis often lives

The history in FUO requires more time and breadth than most other presentations. The key domains are:

Fever characterisation: Onset, documented temperature readings, pattern (continuous, intermittent, cyclical), maximum recorded, response to paracetamol and ibuprofen. Classic patterns are rarely diagnostic in modern practice — but a fever that breaks and recurs on a predictable cycle, or a fever with a characteristic daily spike at the same time, can provide useful clues.

Associated symptoms: Night sweats (tuberculosis, lymphoma, endocarditis), significant unintentional weight loss (malignancy, TB, inflammatory), arthralgia and myalgia (vasculitis, viral, Still’s), rash (viral, drug fever, vasculitis, Still’s, adult-onset Still’s has a characteristic evanescent rash), headache (giant cell arteritis, CNS infection), abdominal pain, change in bowel habit.

Travel history (exhaustive): Every destination visited within the past twelve months and specific exposures — tick bites, animal contact, freshwater exposure, dietary exposures (unpasteurised dairy, raw meat, seafood), sexual contacts, healthcare exposures, blood transfusion abroad.

Occupational and recreational exposures: Abattoir or livestock work (Q fever, brucellosis), farming (leptospirosis), veterinary (multiple), healthcare (tuberculosis, hepatitis, HIV), mining (histoplasmosis in some regions), gardening or spelunking.

Drug and supplement history: Every drug started in the past three months.

Dental and device history: Recent dental work (endocarditis), prosthetic joint, vascular graft, intravascular line, pacemaker.

Examination

A systematic examination is as important as the history. In FUO, it is repeated over time because signs appear at different stages. Key findings include lymph node enlargement (assess all groups — cervical, supraclavicular, axillary, epitrochlear, inguinal), skin rash, petechiae, splinter haemorrhages under the nails (endocarditis), cardiac murmur, hepatosplenomegaly, joint swelling, and temporal artery tenderness. NSW Health’s FUO clinical tool outlines a structured clinical assessment approach.

First-line investigations

Standard first-line investigations (AAFP FUO 2022) include:

  • Full blood count with differential (blasts, atypical lymphocytes, eosinophilia, anaemia)
  • Electrolytes, kidney function, liver function tests, C-reactive protein, erythrocyte sedimentation rate
  • Blood cultures — two to three sets from separate sites, collected before any antibiotic; requesting extended incubation is important if endocarditis is suspected
  • Urine microscopy, culture, and sensitivity; urine pregnancy test in reproductive-age women
  • LDH (lymphoma marker), uric acid, thyroid function tests (subacute thyroiditis)
  • HIV (with consent), syphilis, hepatitis B and C serology
  • Thick and thin blood films plus rapid antigen test for malaria if any relevant travel
  • QuantiFERON-TB Gold or T-SPOT.TB; sputum AFB if respiratory symptoms
  • ANA, ANCA, rheumatoid factor, anti-CCP, complement levels for autoimmune conditions
  • Ferritin — elevated over 10,000 µg/L points toward adult-onset Still’s disease or haemophagocytic lymphohistiocytosis
  • Chest X-ray and abdominal ultrasound as first-line imaging

PET-CT — the recommended next step

When first-line investigations are unrevealing, Wright et al. (2020) recommend PET-CT as the imaging modality of first choice for classic FUO. It identifies areas of abnormal metabolic activity — infection, malignancy, and active inflammation all show increased glucose uptake — and guides more targeted biopsy or tissue sampling. Echocardiography (transthoracic initially, transoesophageal if endocarditis is still suspected after negative TTE) is also important. CT of chest, abdomen, and pelvis is performed where PET-CT is not immediately available or accessible.

C. Australian operations

MBS-funded investigations

Standard FUO workup falls within routine general practice MBS items. Consultations of appropriate length — item 23 (brief), 36 (standard), or 44 (prolonged) — apply. Therapeutic Guidelines provide the most complete AU-specific guidance on FUO investigation. Q fever, Brucella, melioidosis, and leptospirosis serology are sent to specialist microbiology or reference laboratories and may require pathologist consultation for result interpretation.

Notifiable diseases

Many infections that cause FUO are nationally notifiable. If tuberculosis, meningococcal disease, Q fever, leptospirosis, or other notifiable infections are confirmed, your GP or the laboratory notifies the state health department via the National Notifiable Diseases Surveillance System. This is a standard public-health process.

Avoiding premature closure

A consistent theme in FUO management is the danger of anchoring prematurely on a hypothesis. The AAFP guidance (2022) emphasises repeating the history and examination regularly, because signs and symptoms evolve over time. A normal lymph node examination at week two may be abnormal at week four.

D. Special populations

Aboriginal and Torres Strait Islander patients face an under-recognised burden of conditions relevant to FUO — rheumatic heart disease (infective endocarditis risk), higher rates of undiagnosed type 2 diabetes (osteomyelitis and soft-tissue infection risk), tuberculosis re-emergence in some communities, and zoonoses including Q fever and melioidosis in appropriate regions.

Travel-returned patients with new fever should be managed through a specific travel-medicine pathway. Malaria must be excluded with blood films and rapid antigen testing even with a history of antimalarial prophylaxis — no prophylaxis is 100% protective. Therapeutic Guidelines and travel medicine clinics provide current regional risk information.

Immunosuppressed patients with FUO have a much broader and more urgent differential — the threshold for hospital referral is lower, and empirical antifungal or antiviral cover is considered earlier in conjunction with an infectious-diseases specialist.

E. When not to wait

FUO in a stable outpatient is a workup problem. But several features require immediate emergency referral or hospital admission rather than further outpatient investigation:

  • Haemodynamic instability — low blood pressure, rapid heart rate, altered consciousness
  • Suspected meningitis — severe headache, neck stiffness, photophobia, petechiae
  • Immunosuppression plus fever — this is always urgent
  • Pregnancy plus fever — chorioamnionitis and listeriosis are serious
  • Active intravenous drug use plus fever — endocarditis must be assumed until excluded
  • Prosthetic device (joint, valve, vascular graft) plus fever — device infection requires urgent imaging and microbiology
  • Travel from a malaria-endemic region within the past year

When to escalate

Refer or escalate when:

  • First-line GP investigations are unrevealing after two to three visits
  • PET-CT or advanced imaging is required — request through a hospital outpatient or specialist pathway
  • A subspecialty diagnosis is suspected — haematology for possible lymphoma, infectious diseases for complex infection, rheumatology for vasculitis
  • The patient becomes systemically unwell — fever plus haemodynamic instability or rapid deterioration

What this article is and is not

This is general health information drawn from Therapeutic Guidelines, AAFP guidelines (2022), NSW Health clinical tools, and current published evidence. It is not personal medical advice and does not create a doctor–patient relationship. Prolonged fever requires individualised assessment by your GP and, where indicated, specialist input. If you are unwell with fever and uncertain what to do, call HealthLine via HealthDirect (1800 022 222) or go to your nearest emergency department.

For Australian consumer information: HealthDirect — Fever, Better Health Channel.

Sources cited

  1. Durack DT, Street AC — FUO re-examined and redefined (Curr Clin Top Infect Dis 1991)
  2. Wright WF et al. — Fever and FUO review (Open Forum Infect Dis 2020)
  3. AAFP — Fever of Unknown Origin in Adults (Am Fam Physician 2022)
  4. Therapeutic Guidelines (eTG) — Fever / pyrexia of unknown origin
  5. NSW Health Emergency Care Institute — FUO clinical tool
  6. RACGP — Pyrexia of unknown origin
  7. Australian Government — Nationally Notifiable Diseases (NNDSS)
  8. HealthDirect — Fever
  9. Better Health Channel — Fever

Frequently asked questions

  • How long does a fever need to last before it's considered 'fever of unknown origin'?

    The formal definition requires fever of 38 °C or above on multiple occasions for at least three weeks, with no cause identified after a structured workup — traditionally three days inpatient or three outpatient visits. In practice, a fever persisting beyond two to three weeks in an otherwise stable adult warrants structured investigation. Shorter fevers that resolve on their own — the vast majority — are rarely FUO. The three-week threshold exists to exclude the common self-limiting viral illnesses that account for most fever in the community.

  • What are the most common causes of prolonged fever in Australia?

    Infections account for about 30–40% of FUO cases — tuberculosis, infective endocarditis (heart-valve infection, especially in people who use IV drugs or have valve disease), hidden abscesses, and certain viral infections including EBV and CMV. Malignancy — particularly lymphoma — accounts for 20–30%. Non-infectious inflammatory conditions such as vasculitis, adult-onset Still's disease, and sarcoidosis account for another 20%. Zoonotic infections (Q fever from livestock, leptospirosis) are important in rural and regional Australian contexts. In 20–30% of cases, no cause is ever found and the fever resolves.

  • Will I need a PET scan or a bone marrow biopsy?

    Not necessarily as a first step. Your GP starts with blood tests, blood cultures, urine testing, and imaging such as chest X-ray and ultrasound. If those investigations don't find a cause, PET-CT is the current recommended next imaging step — it can identify abnormal metabolic activity in lymph nodes, organs, or bones that point toward lymphoma, infection, or inflammation. Bone marrow biopsy, liver biopsy, or tissue sampling from a specific site may follow if PET-CT identifies a target area. Many cases are diagnosed from the initial workup without needing advanced imaging.

  • Should I take antibiotics while my GP investigates the fever?

    No — not if you are clinically stable. Empirical antibiotics (taking antibiotics without a clear diagnosis) in a stable patient with prolonged fever can mask the cause, interfere with blood culture results, and delay finding the real diagnosis. Your GP will hold off on antibiotics unless a specific bacterial infection is identified or you become unwell enough to require urgent treatment. The goal of the FUO workup is to find the cause, and that requires clean investigations. If you feel significantly unwell, develop instability, or show signs of sepsis, the approach changes — attend emergency immediately.

  • What travel or occupational history matters with a prolonged fever?

    Detailed travel history is crucial. Malaria can cause fever for months after travel to endemic regions; typhoid, dengue, and Q fever also have relevant travel links. In Australia, rural and agricultural exposures matter particularly — Q fever (from cattle, sheep, goats, and kangaroos), leptospirosis (from water contaminated by animal urine), brucellosis (unpasteurised dairy, livestock), and melioidosis (northern Australia, soil and water contact) are all important in the right context. Work in healthcare, abattoirs, veterinary settings, or mining also shapes the differential. Tell your GP every country visited in the past year and any animal, soil, or freshwater exposures.

Source quality

Sources grouped by evidence tier. AU primary tier first; international where AU is silent or lagging; named-author reconstruction where guidelines have not yet caught up. How tiers work.