Infectious Disease Compendium

Fever of Unknown Origin


The classic definition is fevers lasting greater than three weeks in the hospital. Like we can keep people in the hospital for three weeks these days. I remember reading Madeline ("In an old house in Paris/That was covered in vines/Lived twelve little girls/In two straight lines.) to my boys and being struck that Madeline was apparently in the hospital for many weeks for a simple appendectomy. Those were the days of long hospitalizations. These days an appendectomy barely warrants an overnight stay.

But the three weeks is important as most fevers will resolve after 2-3 weeks on their own.

There are different forms of FUO: classic, ICU, AIDS, transplant patients, neutropenic fever vever in the traveler (A NEJM review). Or the " Fever of Unknown Origin or Fever of Too Many Origins? (PubMed)"

Epidemiologic Risks

The diagnosis of the cause of FUO is often made after a careful exposure history. People get what they are exposed to, so any travel, animal and other exposure history is key.


Broadly FUO comes in four categories, with a very partial listing of important causes, and all depends on risks and co-morbidities:

1) Infection: endocarditis, occult abscess, AIDS, extrapulmonary MTb, Cytomegalovirus.

2) Tumor: hematologic malignancies more commonly, sometimes solid tumors like pancreatic, renal cell.

3) Collagen vascular disease: in the young it likely to be SLE, RA or Stills, in the elderly PMR and temporal arteritis.

4) Other: drug, pulmonary embolism, factitious, FMF (the only one that responds to colchicine) and other auto inflammatory diseases (TNF- receptor associated periodic fever, Hyper-IgD with periodic fever, cryopyrin associated periodic syndrome, PFAPA syndrome, TRAPS, FCAPS, Muckle Wells, Schnitzler syndrome (fever, urticaria, paraproteinemia), Crohn's and on and on and on.

These autoinflammatory diseases are a hyper reaction to a trivial stimulus, patients get life long periodic fevers and inflammation with episodes that are symptom free followed by attacks, and are often due to underlying IL-1 beta mutations. Treated with steroids.

Empiric Therapy

None. Find the underlying cause. It is why you get to be called "Doctor".


People lie about sex, drugs and rock and roll, I mean, who really likes Bob Dylan? So always check a VDRL and HIV, even in an 80 year old virgin nun.

The work up of FUO can be slow and tedious. The rule, Suttons Law, is to go where the money is. If the LFT's are up, liver biopsy, if headache LP etc etc.

If there are no findings of IE, and ECHO is a total waste of time. A CT-PET(PubMed) (PubMed) (if you can get it paid for), while having symptoms, may be the best diagnostic test if nothing on screening is indicative of a diagnosis and is superior to a WBC scan (PubMed), but then a WBC scan is almost always a waste of time.

Can also do a 16s rRNA amplification on tissues, beware of getting it paid for. They charged ME for the test.

About 50% of FUO have no diagnosis in modern series, and is usually harmless.

Curious Cases

Relevant links to my Medscape blog


The Benefit of Being Around A Long Time

I Thought It Was a Classic Cause of Fever

Last Update: 07/17/18.