Fever of Unknown Origin

Fever of Unknown Origin

Fever is one of the most common chief complaints in the Peds ED.  We are all very accustomed to the common considerations (ex, UTI, Croup, Bronchiolitis, Appendicitis, and Sinusitis).  We also know there are “zebras” that may try to trample us (ex, Kawasaki’s, Myocarditis, Osteomyelitis, Acute Rheumatic Disease, Lemierre’s, and Cat Scratch Disease). Additionally, we are aware of how important it is to avoid the “It’s Just a Virus” statement. On occasion though, the cause of the fever will not be clear, but the prolonged fever warrants concern. Let us, now, look at Fever of Unknown Origin.

Fever of Unknown Origin: Basics

  • Often confused with “Fever Without a Source
    • Fever of Unknown Origin involves a prolonged duration of fever.
    • Fever Without a Source may become Fever of Unknown Origin, if it lasts long enough.
  • The exact incidence of Fever of Unknown Origin is not well defined.
    • There is no standard definition.
    • The ability to determine etiologies has improved over time.
    • If a diagnosis is eventually determined, then it is no longer of “Unknown Origin.”
  • Definition:
    • Generally requires a duration of fever that is deemed to be excessively long for what was expected.
      • Historically, up to 3 weeks of fever was used. [Petersdorf, 1961]
      • Now, fever lasting longer than 8 days without a source is often cited.
    • Ideally, there are documented fevers (38.0 C; 100.4 F).
  • The Big Categories of Potential Causes to Consider:
    • Infectious – ~30%
      • The proportion of infectious causes has decreased in recent years, likely due to improved diagnostic testing.
    • Rheumatologic / Autoimmune– ~20%
    • Oncologic – ~10%
    • Other Zebras – ~5%
      • Familial Dysautonomia
      • Periodic Fever Syndromes
      • Cyclic Neutropenia
    • Drug Fever – ~5%
      • Often overlooked [Antoon, 2015]
      • First step in evaluation is stopping all nonessential medications [Antoon, 2015]
      • Many agents, including ibuprofen and acetaminophen, can be a source of drug fever.
    • Undiagnosed (often spontaneously resolved) – ~30%

Fever of Unknown Origin: ED Considerations

  • Do not under-appreciate the family’s concern
    • Once we hear that the fever has been present for “2 weeks straight” we may “roll our eyes” internally and immediately think that this is no longer an emergency.  Refrain from this (particularly if you tend to show your inner thoughts readily on your face).
    • This goes along with never saying that it is “just a virus.”
  • General Appearance: Is the child sick or not sick?
    • Sick – Higher risk for badness and you should have lower threshold for hospitalizing.
    • Not Sick – Lower risk for badness (not no risk), but likely more appropriately evaluated as an outpatient.
  • The diagnosis is likely hiding in the History and Physical[Tolan, 2010]
    • Instead of ordering a ton of random tests, ask more questions... even the same ones over again (we have all witnessed “historic alternans”).
    • Additional historic details to obtain:

      • Ethnic Background 
      • Travel history and prophylaxis
      • Animal exposurescats? petting zoos? etc.
      • Vector exposuresticks?
      • HIV and TB risk factors
      • Pica and Dietary exposures
    • Physical exam aspects to include:

  • Look first for Disguised Horses rather than Zebras
    • More likely to be dealing with an unusual presentation of a common condition than a common presentation of an unusual condition. [Antoon, 2015]
    • Consider Pseudo-Fever of Unknown Origin
      • Series of benign, self-limited illnesses over a short period of time [Tolan, 2010]
      • Kids love to get another viral illness just as they are getting rid of one.  This can create the appearance of the child being sick over a protracted course.

Fever of Unknown Origin: Work-up

  • The differential for Fever of Unknown Origin is vast, but resist the urge to order every test available in your hospital.
    • Broad laboratory testing is often more harmful than helpful.
    • The history and physical are the foundation for your Ddx development and subsequent testing strategy.
  • There are some basic tests that are supported by experts and may be useful in your ED to help sort through the Ddx: [Antoon, 2015]
    • CBC w/ Diff – yes, I know that the WBC count is the “last bastion of the intellectually destitute” (Amal Mattu, MD), but ensuring that it is not 125,000 is helpful… plus Hgb and platelet counts are helpful. [Chow, 2011]
    • U/A and UCx
    • CMP
    • Radiographs as indicated
  • Additional testing:
    • Well-appearing
      • Likely appropriate for outpatient evaluation
      • Limit unnecessary testing
      • Arrange for serial examinations and have family keep fever journal.
    • Ill-Appearing
      • Admit
      • Blood Cultures
      • CSF Cultures – if neurologic symptoms present
      • ESR and CRP – have limited value in isolation, but may be helpful to track over time. Normal values do NOT rule-out serious conditions.
      • Categorical Based Evaluations: (likely to be ordered by inpatient team)
        • Infectious
          • Serial Cultures if considering endocarditis
          • Specific antibody and viral testing (ex, EBV)
        • Oncologic
          • Uric Acid
          • LDH
          • Peripheral Smear
        • Rheum/Autoimm
          • ANA, RF
          • C3, C4, CH50
          • Thyroid function panel
          • CRP, ESR, ferritin
        • Immunodeficiency
          • Immunoglobins
          • Lymphocyte markers
          • Antibody titers

Fever of Unknown Origin: Empiric Antibiotics?

  • Ill Appearing?
    • Then have a lower threshold for obtaining cultures and starting empiric antibiotics.
  • Well Appearing?
    • DO NOT give antibiotics!
    • In developed countries, the rates of infectious etiologies of Fever of Unknown Origin have been decreasing.
    • Empiric antibiotics can delay the diagnosis of many conditions like osteomyelitis and endocarditis. [Antoon, 2015; Chow, 2011]


Antoon JW1, Potisek NM2, Lohr JA3. Pediatric Fever of Unknown Origin. Pediatr Rev. 2015 Sep;36(9):380-91. PMID: 26330472. [PubMed] [Read by QxMD]
Tezer H1, Ceyhan M, Kara A, Cengiz AB, Devrim İ, Seçmeer G. Fever of unknown origin in children: the experience of one center in Turkey. Turk J Pediatr. 2012 Nov-Dec;54(6):583-9. PMID: 23692783. [PubMed] [Read by QxMD]

Chow A1, Robinson JL. Fever of unknown origin in children: a systematic review. World J Pediatr. 2011 Feb;7(1):5-10. PMID: 21191771. [PubMed] [Read by QxMD]

Tolan RW Jr1. Fever of unknown origin: a diagnostic approach to this vexing problem. Clin Pediatr (Phila). 2010 Mar;49(3):207-13. PMID: 20164070. [PubMed] [Read by QxMD]

Berezin EN1, Iazzetti MA. Evaluation of the incidence of occult bacteremia among children with fever of unknown origin. Braz J Infect Dis. 2006 Dec;10(6):396-9. PMID: 17420912. [PubMed] [Read by QxMD]

PETERSDORF RG, BEESON PB. Fever of unexplained origin: report on 100 cases. Medicine (Baltimore). 1961 Feb;40:1-30. PMID: 13734791. [PubMed] [Read by QxMD]
Sean M. Fox
Sean M. Fox

I enjoy taking care of patients and I finding it endlessly rewarding to help train others to do the same. I trained at the Combined Emergency Medicine and Pediatrics residency program at University of Maryland, where I had the tremendous fortune of learning from world renowned educators and clinicians. Now I have the unbelievable honor of working with an unbelievably gifted group of practitioners at Carolinas Medical Center. I strive every day to inspire my residents as much as they inspire me.

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