Fever of Unknown Origin

Fever of unknown origin (FUO) is prolonged illness with fever that does not have a known cause even after doing intensive evaluation and diagnostic testing.

Fever of unknown origin (FUO) should be defined only when

  1. Fever ≥38.3°C (≥101°F) on at least two occasions
  2. Illness duration of ≥3 weeks
  3. No known immunocompromised (weak immunity) state
  4. Diagnosis that remains uncertain after a thorough medical history-taking, physical examination, and the following investigations:
    • Determination of erythrocyte sedimentation rate (ESR)
    • C reactive protein (CRP) level
    • Platelet count
    • WBC total count and differential count
    • Measurement of levels of hemoglobin
    • Electrolytes
    • Creatinine
    • Total protein
    • Alkaline phosphatase
    • Alanine aminotransferase
    • Aspartate aminotransferase
    • Lactate dehydrogenase
    • Creatine kinase
    • Ferritin
    • Antinuclear antibodies
    • Rheumatoid factor
    • Protein electrophoresis
    • Urinalysis
    • Blood cultures
    • Urine culture
    • Chest x-ray
    • Abdominal ultrasonography
    • Tuberculin skin test (TST) or
      Interferon γ release assay (IGRA).

Fever of Unknown Origin Approach

The majority of febrile illnesses are short-lived, but fever may persist for weeks or months as part of an infectious disease, inflammatory disorder, or hidden tumor growth.

When fever is caused by infection, the site of infection is an area not easily controlled by host defenses, leading to the continued release of inflammatory cytokines. Likewise, macrophage and lymphocyte involvement in inflammatory disorders causes persistent cytokine production, as do certain tumor growths. This persistent cytokine release is associated with the development of fever.

So it is easy to understand why the majority of cases of classic fever of unknown origin (FUO), loosely defined as lasting longer than 3 weeks despite routine investigation, are found in these three broad categories. 

Miscellaneous and undiagnosed illnesses round out the bulk of fever of unknown origin cases . The proportion of patients in each category varies by geographic location, age, duration of fever, and immune status of the person.

Now a days, more effective molecular diagnostic methods of diagnosing viral and bacterial infections have become readily available. So the proportion of patients with fever of unknown origin in the miscellaneous and undiagnosed categories has increased to about a third of the total in developed countries.

It is important to note that the longer a febrile illness persists without a diagnosis or appropriate therapy, the less likely the fever to be due to an infection.

Bacterial species, particularly Mycobacterium tuberculosis, that causes tuberculosis, make up the largest category of infections that cause prolonged fever of unknown origin. So it is essential to consider tuberculosis as a possible cause of fever of unknown origin. Apart from other tests patient with prolonged fever should undergo tuberculosis tests without a delay.

Other infections causing fever of unknown origin may be localized in cryptic abscesses, especially inside the abdomen (intra-abdominally), or reside on heart valves, where the inflammatory response is blunted.

Persistent viral infections constitute a small percentage of cases of patients with fever of unknown origin. As modern techniques can more readily detect multiple viral infections including Epstein-Barr virus, Cytomegalovirus, and others, it is more easier to detect particular viral infections that are causing the fever than before.

Cytomegalovirus is the most common cause of mononucleosis in adults, and malaria is a common cause of fever in returning travelers. So traveling history is a must to note during the diagnosis procedure of fever of unknown origin.

Malignant (cancer) disease may result in persistent fever due to the production of inflammatory cytokines, necrosis, or the presence of a complicating infection.

Malignant tumor growth showing as fever of unknown origin include lymphomas, leukemias, and solid tumors with metastases to the liver.

Connective tissue disorders may produce fever as a prominent symptom of the illness, including adult Still disease , the leading rheumatologic disorder showing as fever of unknown origin.

Temporal arteritis and polymyalgia rheumatica are seen almost exclusively in patients older than 50 years. So people with prolonged fever who are above 50 years old, temporal arteritis and polymyalgia rheumatica should be considered as a possible cause of fever of unknown origin during the diagnosis procedure.

Sometimes, systemic lupus erythematosus is a cause of fever of unknown origin. Patient needs to undergo the diagnostic tests to rule out other possible causes.

The miscellaneous category of fever of unknown origin includes several various groups of diseases. Granulomatous diseases such as granulomatous hepatitis, Crohn disease, or Sarcoidosis may incite cellular immune responses of our body that result in fever.

Granulomatous hepatitis was present in up to 6% of National Institutes of Health cases with fever lasting longer than 6 months. So, granulomatous hepatitis can be a possible cause of fever of unknown origin.

Chronic pancreatitis, sometime may cause fever of unknown origin, as may recurrent pulmonary embolism.

Chronic Fever in Different Conditions and their percentage


25%-50% cases of fever of unknown origin are due to Infections.

  • Cytomegalovirus
  • Endocarditis
  • Intra abdominal
  • Mycoses
  • Occult abscess
  • Tuberculosis

Malignant Disease

20%-30% cases of fever of unknown origin are due to Malignant diseases.

  • Carcinomatosis
  • Leukemia
  • Local Tumor
  • Lymphoma

Connective Tissue Disease

15%-30% cases of fever of unknown origin are due to Infection connective tissue diseases.

  • Polyarteritis nodosa
  • Rheumatoid arthritis
  • Still disease
  • Systemic lupus erythematosus
  • Temporal arteritis


10%-20% cases of fever of unknown origin are due to other miscellaneous reasons.            

  • Drug induced fever
  • Granulomatous hepatitis
  • Inflammatory bowel disease
  • Pancreatitis
  • Pulmonary Embolism


In 10% to 30% cases of chronic fever remains undiagnosed.

Fever Of Unknown Origin Treatment

Empirical therapeutic trials with antibiotics, glucocorticoids, or
antituberculous drugs should be avoided in fever of unknown origin. It should be given only when a patient’s condition is rapidly deteriorating after the aforementioned diagnostic tests have failed to provide a definite diagnosis.

1. Antibiotics and Antituberculous Therapy

Antibiotic or antituberculous therapy may unalteredly decrease
the ability to culture fastidious bacteria or mycobacteria. Though,
hemodynamic instability or neutropenia is a good indication
for empirical antibiotic therapy.

Also, if the Tuberculin skin test or Interferon γ release assay test is positive or if granulomatous disease is present with absence of normal immune response to antigen (anergy) and sarcoidosis seems unlikely, a trial of therapy for tuberculosis should be started initially. As mentioned earlier, tuberculosis is one of the leading cause of fever of unknown origin, so therapy must be started if it seems rational.

Especially in miliary tuberculosis, it may be very difficult to obtain
a rapid diagnosis. It is important to note that, if the fever does not respond after 6 weeks of empirical antituberculous treatment, then the fever most likely not due to tuberculosis. So in this case, another diagnosis should be considered.

2. Colchicine, Nonsteroidal Anti-Inflammatory Drugs, and Glucocorticoids

Colchicine is highly effective to prevent attacks of familial Mediterranean fever but is not always effective once an attack is well under way or better to say when the fever is already started.

So, when familial Mediterranean fever is suspected to be a possible reason, the fever response to colchicine is not a completely reliable diagnostic tool in the acute phase of the fever, but it is seen that with colchicine treatment most patients show remarkable improvements in the frequency and severity of subsequent febrile episodes within weeks to months.

So, colchicine may be given in patients who show signs and symptoms of familial Mediterranean fever, especially when these patients originate from a high cases region.

If the fever persists and the source remains difficult to diagnose after completion of the later-stage investigations, supportive treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) can be helpful. The response of adult-onset Still’s disease to NSAIDs is dramatic in some cases.

The effects of glucocorticoids on giant cell arteritis and polymyalgia rheumatica are equally impressive. Early empirical trials with glucocorticoids, however, decrease the chances of reaching a diagnosis for which more specific and sometimes life-saving treatment can be more appropriate, such as malignant lymphoma.

The ability of NSAIDs and glucocorticoids to mask fever while permitting the spread of infection or lymphoma dictates that their use should be avoided unless infectious diseases and malignant lymphoma have been largely ruled out and inflammatory disease is probable and is likely to be debilitating or threatening.

3. Anakinra

Interleukin (IL) 1 is a key cytokine in local and systemic inflammation
and the fever response. Specific IL-1- targeting agents has revealed a pathologic role of IL-1-mediated inflammation in a growing list of diseases.

Anakinra which is a recombinant form of the naturally occurring IL-1 receptor antagonist (IL-1Ra), blocks the activity of both IL-1α and IL-1β.

Anakinra is highly effective in the treatment of many autoinflammatory syndromes including familial Mediterranean fever, cryopyrin-associated periodic syndrome, tumor necrosis factor receptor–associated periodic syndrome, mevalonate kinase deficiency (hyper IgD syndrome), and
Schnitzler syndrome.

There are many other chronic inflammatory disorders in which anti-IL-1 therapy is highly effective. A therapeutic trial with anakinra can be considered in patients whose fever of unknown origin has not been diagnosed after later-stage diagnostic tests.

Although most chronic inflammatory conditions without a known basis can be controlled with glucocorticoids, monotherapy with IL-1 blockade can provide improved control without the metabolic, immunologic, and
gastrointestinal side effects of glucocorticoid administration.

Fever of Unknown Origin Outcome

Fever of unknown origin-related mortality rates have continuously declined over the past decades. It is true that majority of fever cases are caused by diseases that are treatable.

So the risk of death related to fever of unknown origin is, of course, dependent on the underlying disease. In a research study, it is found that none of 37 fever of unknown origin patients without a diagnosis died during a follow-up period of at least 6 months; 4 of 36 patients with a diagnosis died during follow-up as a result of infection or malignancy. So the cause behind the fever of unknown origin determines the long term outcome.

A large study on the outcome of fever of unknown origin (Vanderschueren et al, 2014) included 436 patients. In this study a mortality rate was documented as 10%, of which 68% was related to the febrile illness—malignancy in most cases.

In this study, only 4 of 168 patients in whom no diagnosis could be made died, all during their first hospital admission. In two of these patients, diagnosis (lymphoma and pneumonia) was made during autopsy.

Other studies have also shown that malignancy accounts for most fever of unknown origin-related deaths.

Non-Hodgkin’s lymphoma carries a disproportionately high death rates. In nonmalignant cases of fever of unknown origin, fatality rates are very low.

The good long term outcome in patients without a diagnosis confirms that potentially lethal hidden diseases are very unusual and that empirical therapy with antibiotics, antituberculous agents, or glucocorticoids is rarely required in stable patients. In less affluent regions, infectious diseases are still a major cause of fever of unknown origin, and outcomes may be different.

So, the cause of fever of unknown origin, presence of other underlying medical conditions, overall immune status of the body, age of the patient, geographic location of living – all these play an important role in the long term outcome of fever of unknown origin.


  1. Goldman-Cecil Medicine (From Page 3076 to Page 3080)
  2. Harrison’s Principles of Internal Medicine 20th edition (Page 114 to Page 121)
  3. Guyton and Hall Textbook of Medical Physiology
  4. Davidson’s Principles and Practice of Medicine 23rd edition
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