OVERVIEW

What is fever of unknown origin?

Fever of unknown origin (FUO) refers to a prolonged febrile illness whose cause remains undetermined after thorough evaluation and diagnostic testing.

In 1961, Petersdorf and Beeson formally proposed the definition and classification of "fever of unknown origin" (FUO) based on observations of a series of patients with unexplained fever. This concept remains in use today as the classic definition of FUO (in adults), which includes:

• Multiple temperature measurements exceeding 38.3°C;
• Fever lasting for at least 3 weeks;
• Failure to establish a diagnosis after one week of inpatient investigation.

Identifying the underlying cause is key to treatment. Blind use of broad-spectrum antibiotics, antipyretics, or even glucocorticoids solely to control fever is not recommended. Adequate hydration and nutrition should be maintained during the febrile period.

Is fever of unknown origin common?

The proportion of undiagnosed FUO cases exceeded 75% in the 1930s but dropped to less than 10% by the 1950s.

Advances in science and technology have significantly improved and facilitated the differential diagnosis and treatment of FUO. As a result, true FUO cases are now relatively rare, though the exact incidence remains unknown.

SYMPTOMS

What are the types of fever of unknown origin?

Fever of unknown origin can be classified into classic fever of unknown origin and fever of unknown origin in special populations.

Fever of unknown origin in special populations includes fever of unknown origin in hospitalized patients, fever of unknown origin in neutropenic patients, and fever of unknown origin in HIV-infected individuals.

• Classic fever of unknown origin: Fever lasting more than 3 weeks, with oral temperature ≥ 38.3°C on at least three occasions (or temperature fluctuations > 1.2°C within a day on at least three occasions), and no diagnosis confirmed after at least 1 week of systematic and comprehensive outpatient or inpatient investigations. Comprehensive examinations should include at least complete blood count, urinalysis, stool routine, fecal occult blood test, liver function, kidney function, electrolytes, blood cultures, chest X-ray, and abdominal ultrasound. The patient should have no history of immunodeficiency-related diseases.

• Fever of unknown origin in hospitalized patients: The patient had no fever at admission but developed fever for more than 3 days during hospitalization, with oral temperature ≥ 38.3°C on at least three occasions (or temperature fluctuations > 1.2°C within a day on at least three occasions).

• Fever of unknown origin in neutropenic patients: The patient has neutropenia (neutrophil count < 0.5×10⁹/L); fever lasting more than 3 days, with oral temperature > 38.3°C (or temperature fluctuations > 1.2°C within a day); and negative culture results from body fluid specimens after > 48 hours.

• Fever of unknown origin in HIV-infected individuals: Confirmed HIV infection, with fever lasting more than 3 days in hospitalized patients or more than 3 weeks in outpatients, and oral temperature > 38.3°C (or temperature fluctuations > 1.2°C within a day).

CAUSES

What are the possible causes of fever of unknown origin?

Although the specific cause of fever of unknown origin (FUO) cannot be determined, possible causes can still be categorized into the following groups:

• Infection: Various pathogen infections are the most common cause of FUO. Attention should be paid to deep-seated infections, such as abdominal, pelvic, or intracranial infections, infective endocarditis, odontogenic infections, pyelonephritis, and sinusitis. Commonly overlooked pathogens include tuberculosis, non-tuberculous mycobacteria, Listeria, Brucella, Legionella, Salmonella typhi, and Nocardia. Rare pathogens include Q fever, babesiosis, Lyme disease, anaplasmosis/ehrlichiosis, etc.

• Non-infectious inflammatory diseases: Common conditions include systemic lupus erythematosus, giant cell arteritis/polymyalgia rheumatica, rheumatoid arthritis, systemic vasculitis, and inflammatory bowel disease. Rare conditions include adult-onset Still's disease, familial Mediterranean fever (FMF), hyperimmunoglobulin D syndrome, and Blau syndrome.

• Neoplasms: Common malignancies include lymphoma, preleukemia, renal cell carcinoma, and pancreatic cancer. Rare conditions include systemic mastocytosis and atrial myxoma.

• Others: Subacute thyroiditis, factitious fever, adrenal insufficiency, Mollaret's meningitis, Caroli disease, infantile cortical hyperostosis (Caffey disease), etc.

DIAGNOSIS

How to Diagnose Fever of Unknown Origin?

The diagnosis of fever of unknown origin (FUO) is largely one of exclusion. It is typically made only after other potential causes of fever have been ruled out, and the fever remains unexplained. In some cases, diagnostic treatment may be necessary to aid in the diagnosis.

First, doctors should obtain as detailed a medical, family, and exposure history as possible:

• Familial fever may suggest autoinflammatory diseases such as familial Mediterranean fever, hyperimmunoglobulin D syndrome, or Blau syndrome.

• Exposure to seawater or pool water raises suspicion for nontuberculous mycobacteria; contact with cattle or goats suggests brucellosis; a history of tick bites may indicate Q fever or Lyme disease.

Second, doctors should perform a comprehensive and systematic physical examination:

• Do not overlook details such as eyelids, nail beds, temporal arteries, oral cavity, mastoid/sinuses, heart murmurs, genitalia, and anus. Skin pustules, testicular palpation in males, and digital rectal exams are often missed.

• Petechiae or ecchymoses may suggest viral infections or infective endocarditis; skin infections may indicate Nocardia; testicular abnormalities often point to brucellosis or polyarteritis nodosa; anal lesions may suggest inflammatory bowel disease.

Third, comparing changes in the patient's condition over time is crucial:

• For example, a new or changing heart murmur may indicate infective endocarditis—sometimes more reliably than transthoracic echocardiography.

• Progressive enlargement of the liver or spleen often suggests specific infections, lymphoma, or leukemia.

Finally, the correct diagnostic testing strategy should be selected:

• Avoid indiscriminate testing from the outset. Instead, perform targeted routine tests based on history and physical findings, such as common pathogen tests, blood cultures, procalcitonin, transthoracic echocardiography, or antinuclear antibody panels.

• If routine tests are inconclusive, further investigations may include rare pathogen testing, thyroid function tests, bone marrow cytology, lymph node biopsy, or transesophageal echocardiography.

• Advanced imaging such as PET-CT or PET-MRI may be considered if needed.

TREATMENT

Which department should I visit for fever of unknown origin?

Generally, you should see the infectious diseases department or respiratory medicine department.

How to treat fever of unknown origin?

• Identifying the cause is key: Blindly using broad-spectrum antibiotics, antipyretics, or even glucocorticoids to control fever is not recommended, as this often misleads subsequent diagnosis and treatment. For example, antibiotic treatment reduces the diagnostic rate of blood cultures and tissue biopsies. Hidden abscesses may temporarily improve with antibiotics, but fever can rebound after stopping the medication, potentially leading to bacterial resistance. Drainage of the infection site is necessary for a complete resolution.

• For suspected glucocorticoid-sensitive conditions like rheumatic diseases, a clear diagnosis and careful assessment of potential pathogen infections should be made before considering hormone therapy.

• Fever patients should ensure adequate hydration and proper nutritional support. Malnutrition hinders recovery.

DIET & LIFESTYLE

What should patients with fever of unknown origin pay attention to in their diet?

• Ensure adequate fluid intake: Fever can cause significant fluid loss, so it's essential to replenish enough water while also paying attention to electrolyte balance. Functional beverages can be consumed.
• Provide proper nutritional support: Prolonged fever can lead to physical exhaustion, so sufficient nutrient intake is crucial for recovery. The diet should be light, easy to digest, yet nutritionally comprehensive and balanced, with a reasonable mix of meat and vegetables.
• Maintain food hygiene: Avoid raw or overnight leftovers.

What should patients with fever of unknown origin pay attention to in daily life?

• Prioritize rest and avoid overexertion.
• When body temperature rises, patients may feel cold—keep warm. After the fever peaks, they may feel hot—focus on cooling down. Air conditioning can be used to maintain comfort.
• Bathing and hair washing are allowed, but ensure warmth and dry off promptly.

PREVENTION

How to Prevent Fever of Unknown Origin?

The cause is unknown, making prevention difficult. The following measures can reduce the risk of infection-related fever:

• Wash hands frequently with soap or hand sanitizer.
• Ventilate indoor spaces regularly by opening windows.
• Maintain personal hygiene.
• Pay attention to food hygiene.
• Avoid crowded and enclosed public places.
• Maintain a balanced diet and exercise to strengthen immunity.
• Get vaccinated, such as flu or pneumonia vaccines.