What causes unexplained fever? An expert guide

According to the American Academy of Family Physicians, fever of unknown origin (FUO) can be a significant diagnostic challenge. An unexplained fever is defined as a temperature over 101°F (38.3°C) that lasts for several weeks without a clear diagnosis despite extensive testing.

Quick Summary

Several distinct categories of conditions are known to cause a prolonged, unexplained fever, including infections, autoimmune disorders, and malignancies, though in a significant number of cases, a definitive diagnosis is never identified. A thorough evaluation involving a detailed medical history and targeted tests is crucial for identifying the underlying issue.

Key Points

• Diverse Causes: Unexplained fever, or Fever of Unknown Origin (FUO), is caused by a variety of conditions, most commonly infections, malignancies, and non-infectious inflammatory diseases.

• Thorough Evaluation: A diagnosis requires a detailed patient history, repeat physical exams, blood tests, and advanced imaging such as CT or PET scans.

• Infection is Key: Infections, especially atypical or deep-seated ones like tuberculosis or abscesses, are a primary cause of prolonged fever.

• Autoimmune Link: Autoimmune and inflammatory conditions such as Adult Still's disease, lupus, and temporal arteritis are also significant contributors to FUO.

• Malignancy Risk: Certain cancers, including lymphomas and leukemias, can manifest with a persistent, unexplained fever.

• Watchful Waiting: Many cases of FUO never receive a definitive diagnosis but resolve on their own, especially in clinically stable patients.

• Medical Consultation: If a fever lasts for more than three weeks or is accompanied by severe symptoms, it is essential to seek medical attention to investigate potential causes.

Fever of unknown origin: The diagnostic challenge

A fever is a natural response by the body's immune system to fight off an infection or other illness. While most fevers resolve on their own, a persistent, unexplained fever, known as a fever of unknown origin (FUO), can indicate a more complex medical issue. The medical community categorizes FUO to help narrow down the potential root causes, which are grouped into four main areas: infections, malignancies, non-infectious inflammatory diseases, and miscellaneous conditions. The prevalence of each category can vary by patient characteristics and geographic location.

Infections

Infections are among the most common causes of FUO, though many present atypically or are difficult to detect with standard tests. A prolonged fever can be a sign that the body is fighting a deep-seated or unusual infection. Examples include:

• Tuberculosis (TB): Particularly in its extrapulmonary form, which affects organs outside the lungs.
• Intra-abdominal or pelvic abscesses: Pockets of pus that may be hidden deep inside the body.
• Subacute bacterial endocarditis: An infection of the heart's inner lining or valves that may not produce an obvious murmur initially.
• Viral infections: Viruses such as Cytomegalovirus (CMV), Epstein-Barr virus (EBV), and HIV can cause persistent fever.
• Tick-borne diseases: Conditions like Lyme disease can sometimes manifest as a fever that is not easily diagnosed.
• Other infections: Brucellosis, Q fever, and certain fungal infections are also known culprits.

Non-infectious inflammatory diseases

These are conditions where the immune system mistakenly attacks the body's own healthy tissues. They are a significant cause of FUO, particularly in older adults.

• Adult Still's disease: A form of inflammatory arthritis that can cause fever, rash, and joint pain.
• Temporal arteritis: An inflammation of the arteries in the head, more common in those over 60, which may also cause headaches and vision issues.
• Rheumatoid arthritis and Systemic Lupus Erythematosus (SLE): Autoimmune diseases that can cause inflammation throughout the body, triggering a fever.
• Sarcoidosis: A disorder that causes inflammation in various organs, such as the lungs, lymph nodes, and liver.
• Crohn's disease: An inflammatory bowel disease that can sometimes present with a prolonged fever, even without typical abdominal symptoms.

Malignancies

Certain cancers can trigger a fever as the immune system responds to the cancer cells. A fever can be an early or even the only symptom of some malignancies.

• Lymphoma: Both Hodgkin's and non-Hodgkin's lymphoma are commonly associated with FUO.
• Leukemia: Cancers of the blood and bone marrow can cause persistent fever.
• Renal cell carcinoma: A form of kidney cancer that can sometimes manifest as an unexplained fever.
• Metastatic cancer: Cancer that has spread from its original site to other parts of the body can also lead to fever.

Miscellaneous and undiagnosed causes

In many cases, the cause of the fever may be drug-induced, or the diagnosis may never be determined. This can be frustrating for both patients and doctors, but it's important to remember that many undiagnosed FUOs resolve on their own with a positive long-term outcome.

• Drug fever: A hypersensitivity reaction to medication, such as antibiotics or antihistamines.
• Deep vein thrombosis (DVT) and pulmonary embolism (PE): Blood clots can cause a fever.
• Thyroiditis: An inflammation of the thyroid gland.
• Factitious fever: A psychological condition where a person intentionally causes or fakes a fever.

Diagnostic approach and evaluation

When a fever persists without an obvious cause, a healthcare provider will conduct a thorough investigation, starting with a comprehensive history and physical exam. This initial evaluation aims to uncover any subtle clues that might point toward a specific etiology. Further testing is often guided by the patient's symptoms and risk factors, rather than a broad, unfocused approach.

Initial blood tests

• Complete blood count (CBC)
• Complete metabolic panel
• Blood cultures
• Erythrocyte Sedimentation Rate (ESR) and C-reactive protein (CRP)
• HIV test

Imaging studies

• Chest X-ray to check for lung issues like TB.
• CT scans of the abdomen and pelvis to look for hidden abscesses or malignancies.
• Specialized imaging like PET/CT scans may be used in more complex cases to detect areas of inflammation or cancer.

Other tests

• Echocardiogram if subacute bacterial endocarditis is suspected.
• Tissue biopsies (e.g., bone marrow, lymph node, temporal artery) if the diagnosis remains elusive after non-invasive tests.

Management and outlook

In clinically stable patients, doctors typically avoid prescribing antibiotics or steroids without a definitive diagnosis, as this can interfere with diagnostic efforts. If the cause is identified, the underlying condition is treated. For example, specific antibiotics for bacterial infections or steroids for autoimmune disorders. In many cases, especially when a cause is not found, the fever resolves on its own.

Cause Category	Common Conditions	Diagnostic Approach
Infections	Abscesses, TB, Viral infections (CMV, EBV, HIV), Lyme disease, Endocarditis	Blood cultures, imaging (CT, chest X-ray), targeted serology, biopsies
Inflammatory Diseases	Adult Still's disease, Temporal arteritis, SLE, Sarcoidosis, Crohn's disease	Blood tests (ESR, CRP, ANA), imaging (PET/CT), biopsies
Malignancies	Lymphoma, Leukemia, Renal cell carcinoma, Metastatic cancer	Blood tests (LDH), imaging (CT, PET/CT), biopsies
Miscellaneous	Drug fever, DVT, Thyroiditis, Factitious fever	Medication review, imaging (Venous Doppler), hormone tests, observation

It is crucial to remember that a fever that persists for weeks, even if it is low-grade, warrants a medical evaluation. For authoritative information on various health topics, including infectious diseases, refer to reliable sources like the Centers for Disease Control and Prevention.

Conclusion

Unexplained fever is a complex medical issue that requires a diligent and systematic diagnostic approach. The causes are diverse and can range from common infections to more serious conditions like autoimmune diseases and cancers. While many cases resolve spontaneously without a diagnosis, a thorough evaluation is necessary to rule out significant underlying problems. Consulting a healthcare professional is the most important step for anyone experiencing a prolonged or recurrent fever without a clear cause.

Frequently Asked Questions

What is the medical definition of unexplained fever?

Medically, an unexplained fever is often referred to as a Fever of Unknown Origin (FUO), defined as a temperature of over 101°F (38.3°C) that persists for more than three weeks with no known cause, despite extensive evaluation.

Can infections cause prolonged unexplained fevers?

Yes, infections are a common cause of FUO. They can include deep-seated infections like abscesses, tuberculosis, and viral illnesses such as CMV and EBV, which can evade initial diagnostic efforts.

How are autoimmune diseases related to unexplained fever?

Autoimmune conditions can trigger a persistent fever because the body's immune system attacks its own healthy tissue, causing widespread inflammation. Conditions like Adult Still's disease and systemic lupus erythematosus are prime examples.

Can cancer be the cause of an unexplained fever?

Yes, certain types of cancer, especially lymphomas and leukemias, can cause a fever as the body's immune system reacts to the malignancy.

What tests are typically done to diagnose unexplained fever?

Initial tests often include blood work (CBC, ESR, CRP), cultures, and a chest X-ray. If necessary, more advanced imaging like CT or PET scans and targeted biopsies may be performed.

Is it possible for the cause of an unexplained fever to never be found?

Yes. A definitive diagnosis is never confirmed in a significant percentage of FUO cases. Many of these fevers eventually resolve on their own without treatment.

When should I see a doctor for a persistent fever?

You should see a doctor if a fever persists for more than three weeks, or if it is high and accompanied by other severe symptoms like a stiff neck, confusion, a rash, or difficulty breathing.