Fever of Unknown Origin (Pyrexia of Unknown Origin): Causes, Investigations and Management

 Have you ever wondered why someone can have a fever for several weeks without doctors being able to identify the cause immediately?

Fever is one of the most common reasons people visit hospitals and clinics. In many cases, the cause is easily identified, such as malaria, a urinary tract infection or a respiratory tract infection. However, some patients continue to experience fever even after several medical examinations and investigations, without a clear explanation.

This condition is known as Pyrexia of Unknown Origin (PUO), also called Fever of Unknown Origin (FUO).

Understanding this condition is important because the fever may be associated with an underlying infection, an inflammatory disease, a cancer or another medical condition requiring appropriate treatment.

In this article, we will discuss the meaning, causes, investigations and management of fever of unknown origin.

1. Introduction

Fever is a common clinical symptom that occurs when the body's temperature rises above its normal range, often in response to infection or inflammation.

In many patients, the cause of fever becomes apparent after taking a medical history, performing a physical examination and carrying out appropriate investigations. However, in some individuals, the fever persists without an identifiable cause despite repeated medical assessments.

When this happens, healthcare professionals may consider a diagnosis of fever of unknown origin.

Fever of unknown origin presents a diagnostic challenge because several conditions can produce similar symptoms. These include infections such as tuberculosis, certain cancers, autoimmune diseases and reactions to medications.

Identifying the underlying cause requires a careful assessment of the patient, appropriate laboratory investigations and, where necessary, further imaging or specialised tests.

According to the Merck Manual Professional Edition⁠�, infections remain an important cause of fever of unknown origin, although non-infectious conditions must also be considered.

2. Definition of Fever of Unknown Origin

Fever of unknown origin is a condition in which a patient experiences a persistent or recurrent fever without an established diagnosis despite appropriate medical evaluation.

A widely used definition of classic fever of unknown origin includes:

A documented temperature of 38.3°C (101°F) or higher on several occasions.

Fever that persists for more than three weeks.

Failure to establish a diagnosis despite an appropriate period of investigation.

The exact criteria used may vary according to the clinical setting and the patient's circumstances. Current definitions emphasise persistent fever and an unrevealing diagnostic evaluation rather than relying solely on a fixed duration of investigation. �

AAFP +1

It is important to understand that fever of unknown origin is not a disease in itself. Rather, it describes a clinical situation in which the underlying cause of the fever has not yet been identified.

The aim of further evaluation is to determine the condition responsible for the fever and provide appropriate treatment.

3. Causes of Fever of Unknown Origin

The causes of fever of unknown origin can be grouped into four major categories:

Infections.

Malignant diseases.

Inflammatory and rheumatic diseases.

Miscellaneous causes.

Some patients may remain without a definitive diagnosis despite thorough investigation.

The frequency of these causes varies depending on factors such as geographical location, age, medical history and the investigations available. �

Merck Manuals

A. Infections

Infections are among the most important causes of fever of unknown origin.

Some infections may remain undetected during the initial assessment because they produce few localising symptoms or require specialised investigations.

Examples include:

1. Tuberculosis (TB)

Tuberculosis can cause prolonged fever, night sweats, weight loss, fatigue and persistent cough. However, some patients, particularly those with infection outside the lungs, may not have the typical respiratory symptoms.

2. Pyogenic abscesses

An abscess is a collection of pus within body tissues. Deep-seated abscesses may occur in organs or spaces such as the liver, pelvis and abdomen.

These infections can produce persistent fever without obvious external signs.

3. Infective endocarditis

Infective endocarditis is an infection of the inner lining of the heart, usually involving the heart valves.

It may present with prolonged fever, fatigue, a heart murmur and other symptoms. Blood cultures and echocardiography are important investigations when this condition is suspected.

4. Human immunodeficiency virus (HIV) infection

HIV infection may cause prolonged fever, fatigue, weight loss and enlarged lymph nodes. In people with advanced immune suppression, opportunistic infections may also cause persistent fever.

5. Epstein–Barr virus and cytomegalovirus infections

These viral infections may produce prolonged fever, tiredness and other symptoms resembling a glandular fever-like illness.

6. Other infections

Other possible causes include brucellosis, toxoplasmosis, Lyme disease in relevant geographical settings, and certain less common infections associated with travel or specific exposures.

The possibility of malaria and other locally prevalent infections should also be assessed according to the patient's history and clinical presentation.

B. Malignant Diseases

Certain cancers can cause prolonged fever, sometimes before other symptoms become obvious.

Examples include:

1. Lymphoma

Lymphoma is a cancer affecting the lymphatic system. It may cause persistent fever, night sweats, unexplained weight loss and enlarged lymph nodes.

2. Leukaemia

Leukaemia is a cancer involving blood-forming tissues. Patients may experience fever, fatigue, recurrent infections, pallor, unexplained bruising or bleeding.

3. Renal cell carcinoma

This is a type of kidney cancer. Some patients may develop fever, weight loss, blood in the urine or pain in the side of the abdomen.

4. Hepatocellular carcinoma

Hepatocellular carcinoma is a primary cancer of the liver. It may be associated with fever, weight loss, abdominal discomfort and other features of liver disease.

The presence of persistent fever does not automatically mean that a patient has cancer. Further investigations are required to establish the diagnosis.

C. Inflammatory and Rheumatic Diseases

Some conditions cause fever through inflammation rather than an active infection.

Examples include:

1. Adult-onset Still's disease

This is an inflammatory disorder that may cause recurrent fever, joint pain, muscle pain, sore throat and a characteristic skin rash.

2. Rheumatoid arthritis

Rheumatoid arthritis is a chronic inflammatory disease that primarily affects the joints. Systemic inflammation may sometimes contribute to prolonged fever.

3. Systemic lupus erythematosus (SLE)

SLE is an autoimmune disease that can affect several organs, including the skin, joints, kidneys and blood.

Fever may occur during periods of active disease, although infection must also be considered.

4. Granulomatosis with polyangiitis

This is a type of vasculitis, meaning inflammation of blood vessels. It can affect the respiratory tract, kidneys and other organs.

5. Giant cell arteritis

Giant cell arteritis is an inflammatory condition affecting medium and large arteries. It occurs mainly in older adults and may cause fever, headache, scalp tenderness, jaw pain and visual disturbances.

New visual symptoms in a patient with suspected giant cell arteritis require urgent medical assessment because vision loss can occur.

6. Polymyalgia rheumatica

This condition mainly affects older adults and commonly causes pain and stiffness around the shoulders and hips. It may also be associated with systemic symptoms, including fever.

D. Miscellaneous Causes

Some causes of prolonged fever do not fall directly into the categories of infection, malignancy or systemic rheumatic disease.

Examples include:

1. Drug fever

Certain medications can cause fever as an adverse reaction. A careful review of prescribed medicines, over-the-counter products and recently started treatments may help identify the cause.

Patients should not stop essential prescribed medication without medical advice.

2. Thyrotoxicosis

Thyrotoxicosis occurs when there is excessive thyroid hormone activity in the body. Symptoms may include a rapid heartbeat, sweating, tremors, weight loss and heat intolerance.

3. Inflammatory bowel disease

Conditions such as Crohn's disease and ulcerative colitis cause chronic inflammation of the digestive tract. Fever may occur during active inflammation or when complications develop.

4. Sarcoidosis

Sarcoidosis is an inflammatory disease characterised by the formation of small collections of inflammatory cells called granulomas in affected tissues.

It commonly affects the lungs and lymph nodes but can involve other organs.

5. Granulomatous hepatitis

This refers to inflammation of the liver associated with granuloma formation. Several underlying conditions, including certain infections and inflammatory diseases, may be responsible.

6. Factitious fever

Factitious fever refers to fever that is deliberately produced or falsely represented by an individual. It is uncommon and should only be considered after a careful, objective medical evaluation.

7. Familial Mediterranean fever

This is an inherited autoinflammatory condition that can cause recurrent episodes of fever, abdominal pain, chest pain and joint pain.

Despite thorough investigation, some patients with fever of unknown origin may not receive a definitive diagnosis.

4. Investigations

The investigation of fever of unknown origin aims to identify the underlying cause while avoiding unnecessary tests.

A detailed medical history and physical examination are essential. The examination should also be repeated when necessary because new symptoms or physical signs may develop over time.

Investigations are usually performed in stages, beginning with common laboratory tests and progressing to specialised investigations according to the clinical findings.

A. First-Line Investigations

The following investigations are commonly considered in the initial evaluation of an adult with suspected fever of unknown origin.

1. Full Blood Count (FBC)

A full blood count measures the different types of blood cells, including red blood cells, white blood cells and platelets.

It may help identify signs of infection, anaemia, blood disorders or possible malignancy.

A differential white blood cell count and peripheral blood film may provide additional information.

2. Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP)

These are markers of inflammation.

Elevated levels may indicate infection, an inflammatory disorder or certain malignancies. However, they do not identify the specific cause of the fever.

3. Serum Urea, Electrolytes and Renal Function Tests

These tests help assess kidney function, electrolyte balance and the patient's general medical condition.

4. Liver Function Tests

Liver function tests may reveal abnormalities associated with liver disease, systemic infections, inflammation or other underlying conditions.

5. Blood Glucose

Blood glucose testing helps identify abnormal glucose levels, which may be relevant to the patient's overall assessment and management.

6. Blood Cultures

Blood cultures help detect bacteria or other organisms circulating in the bloodstream.

When indicated, several sets may be collected from separate sites, ideally before antimicrobial treatment is started, provided this does not delay urgent treatment in an unstable patient.

Blood cultures are particularly important when infective endocarditis or bloodstream infection is suspected.

7. Urine Microscopy and Culture

Urine testing can identify evidence of urinary tract infection and other abnormalities.

8. Sputum and Stool Investigations

Depending on the patient's symptoms, sputum or stool may be examined and cultured to investigate possible respiratory or gastrointestinal infections.

9. HIV Testing

HIV testing may be appropriate as part of the evaluation, with the patient's consent and in accordance with relevant testing guidelines.

Additional testing may be needed if acute infection is suspected or the initial test does not adequately exclude it.

10. Chest X-ray

A chest X-ray may help identify abnormalities associated with pulmonary tuberculosis, pneumonia, certain malignancies and other chest conditions.

11. Rheumatological Investigations

Tests such as antinuclear antibodies (ANA) and rheumatoid factor (RF) may be considered when the history, examination or initial results suggest an autoimmune or rheumatic disease.

These tests must be interpreted alongside the clinical findings because a positive result does not necessarily establish the diagnosis.

B. Second-Line Investigations

When first-line investigations fail to identify the cause, further tests may be required.

These should be selected according to the patient's clinical findings and the conditions being considered.

1. Abdominal Imaging

Ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI) may help detect deep-seated abscesses, enlarged organs, abnormal lymph nodes or possible malignancies.

2. Echocardiography

Echocardiography uses ultrasound to examine the heart.

It is particularly useful when infective endocarditis is suspected because of positive blood cultures, a heart murmur or other relevant clinical findings.

3. Bone Marrow Examination

Bone marrow aspiration or biopsy may be considered when blood results or other findings suggest a blood disorder, bone marrow disease or certain infections.

4. Liver Biopsy

A liver biopsy may be necessary when investigations suggest a liver condition that cannot be diagnosed through less invasive methods.

5. Temporal Artery Biopsy

In selected older adults with suspected giant cell arteritis, a temporal artery biopsy may help confirm the diagnosis. Treatment should not be delayed when urgent treatment is clinically indicated.

6. Additional Microbiological and Molecular Tests

Depending on the suspected cause, clinicians may request specific serological tests, polymerase chain reaction (PCR) tests, tuberculosis investigations or other specialised microbiological studies.

7. Advanced Imaging

CT of the chest, abdomen and pelvis may be considered in selected patients. Positron emission tomography (PET) may also be useful in particular cases when the diagnosis remains unclear.

The choice of investigation should be guided by the clinical assessment rather than ordering every available test indiscriminately. 

5. Management

The management of fever of unknown origin focuses on identifying and treating the underlying cause.

Because many different diseases can produce prolonged fever, there is no single treatment that is appropriate for every patient.

A. Treat the Underlying Cause

Once the cause has been identified, treatment should be directed towards the specific condition.

Examples include:

Tuberculosis: Appropriate anti-tuberculosis treatment following diagnostic assessment and applicable treatment guidelines.

Bacterial infections: Appropriate antibiotics selected according to the suspected or confirmed organism, infection site and relevant antimicrobial guidance.

HIV infection: Antiretroviral therapy and appropriate management of associated infections when indicated.

Malignancies: Specialist assessment and disease-specific treatment, which may include chemotherapy, radiotherapy, surgery or other appropriate therapies.

Autoimmune and inflammatory diseases: Appropriate anti-inflammatory or immunosuppressive treatment under suitable clinical supervision.

Drug fever: Review and, where appropriate, withdrawal or substitution of the suspected medication under medical supervision.

Thyrotoxicosis: Treatment directed at the underlying thyroid disorder.

Correctly identifying the cause is important because treatments that help one condition may be ineffective or harmful in another.

B. Provide Supportive Care

Supportive care may include:

Encouraging adequate fluid intake when appropriate.

Monitoring body temperature and other vital signs.

Ensuring adequate nutrition and rest.

Using suitable antipyretic medication, such as paracetamol, when clinically appropriate.

Monitoring for complications and deterioration.

Antipyretics can help relieve discomfort, but they do not treat the underlying cause of the fever.

Patients with significant dehydration, severe weakness or other concerning symptoms may require hospital assessment and supportive treatment.

C. Avoid Unnecessary Empirical Treatment

Empirical treatment means starting treatment before the cause has been confirmed.

In a clinically stable patient with fever of unknown origin, routine use of broad-spectrum antibiotics or corticosteroids without an appropriate indication may obscure the diagnosis, expose the patient to adverse effects and delay the correct treatment.

However, this does not mean treatment should always be delayed.

If the patient is seriously ill or has signs of sepsis, urgent assessment and appropriate treatment must not be postponed while waiting for every investigation result.

The decision to begin empirical treatment should therefore depend on the patient's clinical condition and the suspected underlying disease.

D. Repeat Clinical Assessment

A patient with fever of unknown origin may develop new symptoms or signs during follow-up.

Repeated history-taking and physical examinations may reveal important findings that were not apparent during the initial assessment.

The healthcare team should review previous test results, assess the patient's progress and determine whether additional investigations are necessary.

E. Refer When Necessary

Patients whose fever remains unexplained despite initial evaluation may require specialist assessment.

Depending on the suspected cause, referral may be appropriate to infectious disease specialists, physicians, rheumatologists, haematologists or oncologists.

The overall approach should be systematic, patient-centred and guided by clinical evidence. 

6. Conclusion

Fever of unknown origin is a clinical condition characterised by persistent or recurrent fever without an established cause despite appropriate medical evaluation.

Its causes are diverse and include infections, malignant diseases, inflammatory and rheumatic conditions, medication reactions and other disorders.

The diagnosis requires a detailed medical history, careful physical examination and appropriate investigations. First-line tests help identify common abnormalities, while specialised investigations may be necessary when the cause remains unclear.

Management depends on the underlying condition, with supportive care and close monitoring playing important roles.

The key message is that persistent fever should never be ignored. Anyone experiencing prolonged or recurrent fever should seek medical assessment rather than relying on self-medication or repeatedly treating the fever without investigating its cause.

Early recognition of the underlying condition can help guide appropriate treatment and improve patient outcomes.

Important Health Notice

This article is intended for health education and general information. It does not replace an individual medical assessment, diagnosis or treatment plan. Anyone experiencing persistent fever should consult a qualified healthcare professional. Seek urgent medical attention if fever is accompanied by confusion, difficulty breathing, collapse, severe headache with neck stiffness, or other signs of serious illness.

References and Further Reading

Merck Manual Professional Edition: Fever of Unknown Origin⁠�

American Family Physician: Fever of Unknown Origin in Adults⁠�

Merck Manual Professional Edition: Some Causes of Fever of Unknown Origin⁠�