What is Fever of Unknown Origin?
“Fever of unknown origin” or FUO, is a term first used by Dr. Petersdorf and Dr. Beesom in 1961. Initially, it described a situation where someone has a high temperature (101 degrees Fahrenheit or 38.3 degrees Celsius) lasting at least three weeks, yet doctors couldn’t find out why, even after conducting tests in the hospital for a week. As medicine evolved, including the development of better testing methods, an increase in people with weakened immune systems (like those with HIV/AIDS), and new treatments, the definition of FUO also changed. Today, we recognize four types of FUO – typical FUO, FUO occurring in hospitals, FUO in patients with reduced white blood cells, and HIV-related FUO.
To diagnose FUO, doctors usually take a detailed medical and physical examination. They may also suggest conducting several tests like blood count, blood cultures, chest X-ray, assessing liver and metabolic health, examining urine and its culture, checking for inflammation markers, specific infection and auto-immune disease indicators, tuberculosis skin test, HIV testing, and a CT scan of the abdomen.
There are over 200 diseases and conditions, including cancers, infections, autoimmune diseases, and others, which can cause FUO. Doctors usually perform tests not directly indicated by patient’s symptoms early in this investigation, which can be misleading and expensive. It’s also crucial to know that despite thorough testing and medical advancements, there are still cases (up to 51%) when doctors can’t pinpoint the cause of FUO, making it a challenging diagnosis.
Note that people with weaker immune systems, including those with HIV, may need a different strategy to identify and treat recurring fevers. However, the information provided here is mainly about FUO in adults with no immune system problems.
What Causes Fever of Unknown Origin?
Fever of unknown origin (FUO) often results from common conditions that don’t typically present with fever. These potential causes can be grouped into categories like infection, inflammatory conditions not caused by infection, cancer, and other miscellaneous causes.
Non-infectious inflammatory causes might include diseases like giant cell arteritis, juvenile rheumatoid arthritis in adults (Adult Still disease), lupus (SLE), periarteritis nodosa/microscopic polyangiitis (PAN/MPA), rheumatoid arthritis, gout, sarcoidosis, some syndromes and diseases.
Infections that might cause a FUO include tuberculosis (TB), Q fever, some types of viral infections like HIV or Epstein-Barr virus, bacterial infections like chronic sinusitis or prostatitis, tick-borne infections, and a few other regional infections.
Cancers that might lead to a FUO include lymphoma, certain types of leukemia, myeloma, different body organ cancers, and uncontrolled growth of white blood cells (malignant histiocytosis).
Miscellaneous causes of FUO can include cirrhosis (scarring of the liver due to long-term damage), fever caused by certain medications (drug fever), inflammation of the thyroid gland (thyroiditis), blood clots in the lungs (pulmonary emboli), and a few other conditions.
Specific groups of people may be more susceptible to particular causes of fever. For example, common causes of fever in elderly people over 65 are often connective tissue diseases. In travellers, fever might more often be caused by infectious diseases like malaria or HIV. In patients who have recently been in a healthcare facility, the cause of fever might be a reaction to a drug, complications after a surgery, blood clot, cancer, reactions related to blood transfusion, or a specific bacteria called Clostridium difficile. Patients with weakened immune systems, often due to conditions or treatments like chemotherapy, might suffer from fever due to infections.
Risk Factors and Frequency for Fever of Unknown Origin
The causes and distribution of Fever of Unknown Origin (FUO) can vary from person to person. It depends on things like what’s causing the fever, the age of the person, where they live, what they’re exposed to in the environment, and their immune or HIV status. In developing countries, FUO is most commonly due to an infectious disease. However, in developed countries, it’s likely caused by a non-infectious inflammation.
Signs and Symptoms of Fever of Unknown Origin
Fever of unknown origin, or FUO, is difficult to diagnose. Doctors usually need detailed information like your past illnesses, symptoms, drinking habits, medications, job exposure, pets, travel, and family health conditions. This helps them narrow down the cause of the fever. For example, if you have symptoms like feeling full too soon and significant weight loss, your doctor might check for cancer. Meanwhile, if you’re experiencing chills, these could point to an infection. Joint problems might suggest a rheumatologic disorder.
These are the key aspects of your history your doctor may ask about:
- Family health history
- Vaccination history
- Dental history
- Work history
- Travel history
- Diet and weight history
- Drug history (including over-the-counter and illegal drugs)
- Sexual history
- Hobbies
- Contact with animals
- Past surgeries, traumas or procedures
Your doctor will want to confirm your fever in a clinic and look for any patterns. Certain fever patterns could be a clue to specific infections, for example:
- Tertian or quartan fever (fever every third or fourth day) in prolonged malaria
- Undulant fever (evening fever and sweats that resolve by morning) in brucellosis
- Week-long fevers with week-long breaks in tick-borne relapsing fever or Pel-Ebstein fever in Hodgkin disease
- Periodic fevers in cyclic neutropenia
- Two fever spikes per day in adult’s Still disease, malaria, or typhoid
If an infection is suspected, past surgeries, TB exposure, pet contacts, insect bites, rodent exposure, blood transfusions, and immunosuppressive drug use will be looked into.
When cancer is considered, doctors might ask questions about your weight loss, family history of cancer, smoking, and alcohol use. If non-infectious conditions are suspected, questions will likely focus on things like muscle and joint stiffness, oral ulcers, and family history of autoimmune conditions.
Other potential causes of FUO include cirrhosis and Crohn’s disease. To identify these, your doctor might ask about your past medical history, alcohol intake, intravenous drug use, non-alcoholic fatty liver disease, and hepatitis.
Testing for Fever of Unknown Origin
When trying to figure out the cause of a fever of unknown origin (FUO), doctors usually suspect a common illness that’s showing up in a different or subtle way, rather than a rare disease. Diagnosing an FUO isn’t easy. It involves a thorough examination of the patient’s medical history and a complete physical check-up.
Non-Invasive Tests
The initial testing often includes:
* A complete blood count, which measures different types of cells in your blood
* A complete metabolic panel, testing for various substances in your blood
* Urine analysis and culture, checking your urine for infections
* Blood cultures, which helps find bacteria or fungal infections in your blood
* A chest X-ray
* Measurement of erythrocyte sedimentation rate (ESR), a test that helps check for inflammation in the body
* A C-reactive protein (CRP) test, another test that measures inflammation
* Tests like lactate dehydrogenase (LDH), creatinine phosphokinase, ANA, rheumatoid factor, tests for cytomegalovirus and heterophile antibodies, and a tuberculin skin test or interferon-gamma release assay that are used to monitor various conditions
* An HIV test
* CT scans of your abdomen and chest
* Cardiac echocardiography, which may be helpful if heart-related conditions like culture-negative endocarditis or atrial myxoma are suspected.
All these tests may not provide a clear diagnosis about what is causing the fever. In such a case, the doctor would rule out any possibility of temperature manipulation and check the list of medications the patient is taking to see if any drug-induced fever could be a possibility.
Nuclear Medicine Tests
Earlier, nuclear medicine tests were only done when routine investigations didn’t give a diagnosis. However, newer studies suggest that positron emission tomography (PET) scans that use a radioactive tracer, fluorodeoxyglucose (FDG), could be performed earlier in the testing process. These scans can detect the site of inflammation, infection, or tumor, although they aren’t very specific. In the absence of FDG-PET scans, labeled leukocyte studies could be an alternative, but they might have a lower diagnostic yield. These tests primarily help in determining the area requiring further targeted evaluation.
Invasive Tests
If non-invasive approaches are not conclusive, some invasive tests, such as biopsies of lymph nodes, liver, bone marrow, an epididymal nodule, and the temporal artery, are conducted. These tests are carried out only if doctors suspect a specific condition based on the initial test results. A biopsy helps in diagnosing conditions like cancer, certain infections, and inflammation that might be causing the FUO.
Further, examinations of the upper and lower gastrointestinal tract might be carried out if doctors suspect conditions like Crohn disease, biliary tract disease, and gastrointestinal tumors. In some patients, Crohn disease, a type of inflammatory bowel disease, might be the underlying cause of the FUO.
Treatment Options for Fever of Unknown Origin
There’s no one-size-fits-all approach to managing ‘fever of unknown origin’ (FUO), due to the many different possible causes. It’s crucial to try and identify and exclude all potential diagnoses. Once a cause is identified, a specific treatment can be started. Generally, antibiotics are not recommended unless the patient has a reduced number of a type of white blood cell (a condition called ‘neutropenia’). This is because antibiotics can sometimes delay the detection of hidden infections. Similarly, glucocorticoids (a type of steroid) are typically not suggested unless there are strong signs pointing to a rheumatic disease.
However, in situations where the patient’s condition is worsening, doctors might consider giving antibiotics, steroids, or medications to treat tuberculosis even if a specific cause hasn’t been found yet. There are also exceptions where treatment with antibiotics or steroids can be started even if the cause is not clear, such as with certain types of heart valve infection or inflammation of blood vessels, or with suspected tuberculosis or other similar infections.
Surgery is uncommon for people with FUO.
Here are a few specific examples of treatment:
- In cases where patients exhibit small growths in the liver (called ‘hepatic granulomas’), about 50% may respond to steroids, while for others, the granulomas may go away by themselves.
- Patients diagnosed with ‘giant cell arteritis’, a condition that inflames the lining of your arteries, are typically treated with high doses of steroids. If the patient is seriously ill or has considerable eye issues, they might receive steroids directly into a vein.
- For ‘polymyalgia rheumatica’, a disorder characterized by muscle pain and stiffness, steroid therapy is the treatment of choice.
- If it seems like medication is causing the fever, stopping that medication is the first step. In this case, the fever should settle down within two days of stopping the drug.
There’s a test that uses naproxen, a type of pain reliever, to help identify whether the FUO could be due to cancer or an infection. During the 3 to 4 days of the test, patient’s temperature is monitored while they’re given naproxen. If the temperature drops considerably, it’s possible that the cause of the FUO might be cancer. Nonetheless, if the temperature stays the same or decreases only a bit, the FUO might be due to an infection. This test isn’t used often because it’s not specific enough to be reliable for every patient.
It’s worth noting that a cause can’t be found in about half of all FUO cases. But the good news is, these patients often have a good outlook, and the FUO often goes away on its own over several weeks to a few months. If a patient is stable but the cause of the fever is still unknown, over-the-counter anti-inflammatory drugs can be used to manage the symptoms.
What else can Fever of Unknown Origin be?
Undiagnosed, ongoing fever, also known as Fever of Unknown Origin (FUO), could be due to many illnesses, which can typically be grouped into four categories: infections, tumors or neoplasms, connective tissue disease, and various other causes. Let’s explore these categories and their possible causes in more detail.
The most common reason for FUO is infections, responsible for about a third of the cases. There is a long list of infections that could be behind the undiagnosed fever:
- Miliary tuberculosis
- Brucellosis
- Q fever
- Abdominal abscesses
- Typhoid fever
- Actinomycosis, a type of bacterial infection
- Amebiasis, a parasitic infection of the intestines
- Atypical mycobacterial infection
- Infections such as Dengue fever, Malaria, Hepatitis A to E, SARS COVID 19, Epstein-Barr virus
- HIV – although it’s worth noting that in the HIV population, FUO is rarely due to the virus itself.
Another third of FUO cases are due to immune system and inflammatory disorders. These could include:
- Adult Still’s disease, an uncommon type of inflammatory arthritis
- Temporal arteritis, a condition causing inflammation of arteries
- Rheumatoid arthritis
- Systemic lupus erythematosus, an autoimmune disease affecting multiple organs
- Sarcoidosis, a disease involving abnormal collections of inflammation affecting multiple body parts
Up to 18% of FUO cases are caused by tumors or neoplasms, abnormal growth of tissue. The most commonly associated tumors include:
- Lymphoma
- Renal cell carcinoma, a type of kidney cancer
- Acute myeloid leukemia, a type of blood and bone marrow cancer
- Colon carcinoma, a type of colon cancer
- Hepatoma, a type of liver cancer
The remaining causes of FUO are classified as miscellaneous. These include:
- Drug-induced fevers
- Liver cirrhosis, a liver disease
- Subacute thyroiditis, an inflammation of the thyroid
- Deep vein thrombosis, a blood clot in a deep vein
- Fictitious fever, where symptoms are manufactured or induced on purpose
All these potential causes underline the importance of comprehensive testing and examination in diagnosing FUO.
What to expect with Fever of Unknown Origin
The outlook for a fever of unknown origin (FUO) – a fever that has lasted longer than usual without a clear reason – can be different for different people. This mainly depends on what is actually causing the fever and any other diseases the person might have. Unfortunately, older adults or people diagnosed with cancer may not fare as well.
Compared to adults, children who have a fever without an obvious cause usually fare better in the long run.
Possible Complications When Diagnosed with Fever of Unknown Origin
Complications can differ depending on the specific diseases that might be causing a condition known as “fever of unknown origin” (FUO). Interestingly, patients whose FUO cause remains unknown often have good results and aren’t reported to experience complications once their fever goes away.
Complications based on various causes of FUO:
- Complications vary based on the specific disease causing FUO
- Patients with no diagnosed cause of FUO often have good outcomes
- No reported complications after fever resolution in undiagnosed FUO cases
Preventing Fever of Unknown Origin
Patients should understand that figuring out the cause of an unexplained fever can be challenging. It’s crucial that patients collaborate closely with their healthcare provider in these situations. By providing a detailed account of their medical history, patients can help their doctors direct their testing in a more targeted way, making it easier to discover the root cause of the fever.
