Definition

Fever of unknown origin (FUO) is a condition where the body temperature reaches 38.3°C, measured rectally. This condition is not caused by temporary, self-limiting diseases; illnesses that do not quickly become severe; or disorders with clear symptoms or signs. It is not accompanied by abnormalities in common examinations like chest X-rays, urine tests, or blood cultures. Currently, FUO is classified into four categories:

• Classic FUO: A fever lasting more than three weeks without an identifiable cause after three days of evaluation in a hospital or three or more outpatient visits.
• Healthcare-associated FUO: A fever in hospitalized patients receiving acute care without an infection or infectious process at admission. If the diagnosis remains unclear after three days of proper evaluation, it falls under this category.
• Neutropenic FUO: A fever in patients with decreased neutrophils (a type of white blood cell) and other immune deficiencies. If the diagnosis remains uncertain after three days of proper evaluation, including negative culture results after 48 hours, it is classified here.
• HIV-related FUO: A fever lasting more than four weeks in confirmed HIV-positive outpatients or more than three days in confirmed HIV-positive inpatients, if the diagnosis remains unclear after proper evaluation.

Causes

The cause of FUO cannot be identified in about 10% of adults. However, FUO causes are usually divided into four categories:

• Infection

The most common cause, accounting for 25-50% of cases. In patients with HIV, infections may be due to tuberculosis, atypical mycobacteria, fungal dissemination, or cytomegalovirus.

• Connective tissue diseases

Around 10-20% of FUO cases stem from connective tissue diseases such as systemic lupus erythematosus, rheumatoid arthritis, giant cell arteritis, polymyalgia rheumatica, thyroiditis, vasculitis, or Adult Still Disease.

• Tumors

The most common tumors causing FUO include lymphoma, leukemia, renal cell carcinoma, ovarian carcinoma, atrial myxoma, Castleman disease, hepatocellular carcinoma, and metastatic carcinoma. However, the incidence of tumor-caused FUO has decreased to 5-35%, likely due to advancements in early detection through ultrasound or CT scans.

• Other causes

Other causes, accounting for 15-25%, include drug reactions, deep vein thrombosis, recurrent pulmonary embolism, sarcoidosis, inflammatory bowel disease, and factitious fever (self-induced fever).

If you want to know more about vasculitis, you can read it here: Vasculitis—Definition, Causes, Symptoms, and Treatment

Risk Factor

Several factors can increase the risk of developing FUO, particularly from infections, including:

• A weakened immune system (due to HIV, cancer, diabetes, or immunosuppressant use)
• Heart abnormalities
• Urinary tract abnormalities
• History of surgeries
• Medical device implants (e.g., IV lines, pacemakers, artificial joints)
• Use of illegal injectable drugs
• High-risk sexual behavior (e.g., unprotected sex, multiple partners)
• Contact with individuals infected with certain diseases like tuberculosis
• Travel to areas endemic with specific diseases
• Smoking
• Alcohol use
• Exposure to chemicals at the workplace
• Family history of inherited diseases that may cause fever

Read more: Tuberculosis (TB) Lung - Definition, Cause, Symptom, And Treatment

Symptoms

FUO is typically accompanied by other symptoms that can help doctors identify the underlying cause.

Typical symptoms of FUO include:

• Body temperature over 38°C in infants or 37.5°C in children and adults
• Sweating
• Chills
• Headaches

Additional symptoms often associated with fever include:

• Body or joint pain
• Weakness and fatigue
• Sore throat
• Cough
• Rashes
• Nasal congestion

Diagnosis

FUO diagnosis is established through medical history taking, physical examination, and additional tests.

Medical Interview

A medical interview is a question and answer session between a doctor and a patient. The doctor will ask about:

• Your symptoms
• Previous medical history
• Family medical history
• Travel history

This information can provide insight into possible underlying causes of FUO.

Physical Examination

After conducting a Q&A, the doctor will perform a physical examination to look for signs that can point to a specific cause.

The doctor will perform a complete examination of the entire body, starting from your overall appearance, skin, vital organs, feet, heart, bones, joints, stomach, thyroid, rectum, lymph nodes, and a pelvic examination. The doctor will also examine your teeth to look for dental infections.

Diagnostic Tests

The doctor will plan further focused examinations based on the findings of the physical examination and medical interview. A specific disease examination, such as one for malaria, will be performed if a particular item is discovered. Doctors typically perform additional supporting examinations in addition to the specific ones listed below:

• Complete blood count with differential
• Erythrocyte sedimentation rate
• Liver function tests
• Serial blood cultures before starting antibiotics
• Antibody and PCR tests for HIV
• Tuberculin or IGRA tests for tuberculosis
• Urine tests and cultures
• Chest X-rays
• Serological tests (e.g., ANA, RF) for autoimmune diseases
• Biopsies for suspected tissue abnormalities

Read more: Erythrocyte Sedimentation Rate - Indications, Contraindications, Results and Recommendations

Management

FUO treatment is based on its cause. Nonsteroidal anti-inflammatory drugs (NSAIDs) and antihistamines can help manage FUO without a clear cause. In many cases, these medications help reduce the fever.

For HIV-related FUO, treatment focuses on managing HIV with antiviral medications, which may resolve HIV-related complications and symptoms.

Complications

FUO complications depend on the underlying cause. Some are harmless, while others may be life-threatening.

Prevention

General prevention tips include:

• Ensuring vaccinations are up to date
• Washing hands frequently with soap and water for at least 20 seconds, especially after using the toilet, before eating, after coughing or sneezing, and before and after handling animals
• Using a 60% alcohol-based hand sanitizer after washing hands
• Avoiding contact with people who have contagious illnesses
• Avoiding touching your face with unwashed hands
• Using protective gear like face masks and gloves when necessary
• Not sharing personal items (e.g., toothbrushes, razors, combs)
• Disinfecting commonly touched surfaces
• Only eating properly cooked food
• Using insect repellents and fumigating regularly

When to See a Doctor?

Contact a doctor if you experience a prolonged fever. Seek emergency medical help if you experience symptoms such as:

• Stiff neck
• Confusion
• Extreme drowsiness
• Chest pain
• Shortness of breath
• Difficulty swallowing
• Repeated vomiting

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