Fever (Pyrexia) Of Unknown Origin (Fuo Or Puo)

Types of Infections & Treatments

About Fever (Pyrexia) Of Unknown Origin (Fuo Or Puo)

Background Information:

Fever of unknown origin is defined as fever that is ongoing for 2 weeks or more and has no cause found after extensive investigations done. With current technology and improved laboratory diagnostic tests, these cases are less frequently seen. The main causes are:

  1. Infections (30 – 40 %)
  2. Neoplasms (20 – 30 %)
  3. Collagen vascular diseases (10 – 20 %)
  4. Miscellaneous (15 – 20 %)
  5. Factitious Fever

The truly unknown causes contribute about 5 – 15 % after extensive investigations. Most eventually resolve and patients remain well with no long term sequelae.


In patients who are more than 50 years old, about 30 % are related to connective tissue / vasculitis of which Giant Cell Arteritis, Polymyalgia Rheumatica constitute about 50 % of cases.

In HIV positive patients, more than 75 % of PUOs are due to infective causes and another 20-25 % due to lymphoma. In the extreme elderly, neoplasms are slightly more common.


The approach to investigating a PUO is like any other conditions. A careful history taking which will include the following clues to the aetiology will help to narrow the focus of investigation and laboratory tests. Attention should be paid to the following:

  • System review to narrow down to the system involved, either chest symptoms or abdominal symptoms or neurologic symptoms etc
  • Fever pattern, how temperature is taken and at what time of day and by whom
  • Associated symptoms like weight loss, night sweats, anorexia, headaches, rashes, etc
  • Travel history especially in otherwise healthy patients
  • Sexual history (including HIV risk factors) especially in younger patients
  • Animal contacts and unusual epidemiological exposures
  • Recent surgeries
  • Recent vaccinations
  • Contact history
  • Family history

In the physical examination, attention should be paid to the severity of fever, pattern, pulse temperature dissociation, associated chills and rigors, in addition to the usual clinical examination.

Investigations are usually done based on clinical suspicion of aetiology. General blood tests should be done first before specialised tests and imaging tests in a systematic manner. More sophisticated scanning, PET scans and radioisotope scans are reserved for more complex and unsolved cases. Invasive procedures are done if there are no answers from the routine tests and these may include bone marrow examination, lumbar punctures and biopsies.


The treatment will depend on the cause of the fever. Sometimes, empiric treatment are necessary if the suspicion is strong but the investigations do not yield a diagnosis, eg. antibiotic or anti-TB treatment may be started if laboratory tests are inconclusive and clinical index is high.

If you do not have an infection as a cause of your fever, you will be referred to the appropriate specialists for further management eg. oncologist if you have a lymphoma or rheumatologist if you have a connective tissue disease.

Points to Note:

Laboratory diagnostic tests are not perfect and are not 100% accurate

  • We do not have a test for every disease or virus but most of those pathogens that are of public health importance or have long term implications on your health can be tested
  • No one single test can be used with absolute certainty to diagnose a disease. Often, we depend on a combination of tests to make a diagnosis
  • Sometimes, we have to resort to trial treatment or empiric treatment if investigative tests are inconclusive. If the patient makes a therapeutic response and feels better, we have achieved our goal
  • In PUO, we are looking for treatable causes and to rule out sinister causes eg. malignancies so that we do not miss opportunities for early treatment or intervention

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