Fever of unknown origin resident survival guide

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Fever of Unknown Origin

Diagnostic Criteria


  • Common Causes
  • Age-Specific Considerations
  • Complete Diagnostic Approach

  • Focused History
  • Physical Examination
  • Laboratory Workup
  • Imaging Study
  • Other Investigation
  • Management

    Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Gerald Chi, M.D.


    Management of fever of unknown origin should generally be withheld until the etiology is ascertained so that treatment can be targeted toward a specific pathology.

    Diagnostic Criteria

    Fever of unknown origin (FUO) may be considered providing all the following criteria are fulfilled:

    • Fever higher than 38.3°C (100.9°F) on several occasions
    • Persisting without diagnosis for at least 3 weeks
    • At least 1 week's investigation in hospital

    Minimum diagnostic evaluation to qualify as FUO includes:[1]


    Common Causes

    Common causes of fever of unknown origin are as follows:[2]

    • Infections
    Intra-abdominal infections
    Urinary tract infections
    Upper respiratory tract infections
    Infected peripheral vessels
    • Neoplasia
    Lymphoproliferative disorders
    Myelodysplastic syndrome
    Solid tumors
    • Rheumatic disorders
    Adult onset Still's disease
    Giant cell arteritis
    Polymyalgia rheumatica
    Other forms of vasculitis (e.g., polyarteritis nodosa, Wegener's granulomatosis, Takayasu's arteritis)
    Other rheumatologic disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome)
    • Endocrine disorders
    Adrenocortical insufficiency
    Granulomatous disorders
    Vascular disorders (e.g., pulmonary embolism, hematoma)
    Drug fever

    Age-Specific Considerations

    Respiratory tract infections cause FUO in infants more often than in children older than 12 months, whereas connective tissue diseases predominate as the cause of FUO in children and adults.[3] For patients older than 65 years, non-infectious inflammatory disorders including polymyalgia rheumatica and temporal arteritis are identified as the major causes of FUO in developed countries. Intra-abdominal abscesses, complicated urinary tract infections, tuberculosis, and endocarditis are the most common infectious causes of FUO in the elderly.[4][5]

    Complete Diagnostic Approach

    Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete blood count; CMV, cytomegalovirus; DC, differential count; HIV, human immunodeficiency virus; PET, positron emission tomography; s/o, suggestive of; SMA-7, sequential multiple analysis-7.

    Suspected Fever of Unknown Origin

    • Fever higher than 38.3°C (100.9°F) on several occasions
    • Persisting without diagnosis for at least 3 weeks
    • At least 1 week's investigation in hospital

    Focused History

    • Verify the presence of fever and its pattern[6][7]
    • History of previous surgeries or procedures
    • History of malignancy and related therapy
    • History of previously treated infections
    • History of sick or animal contacts
    • History of psychiatric illness
    • History of recent traveling
    • History of comorbidities
    • History of medications
    • History of transfusions
    • Social and family history

    Physical Examination














    Imaging Study

    Chest Radiograph

    • Chest radiograph should be considered as a part of the initial diagnostic workup.


    • Echocardiography should be considered when suspecting endocarditis.

    Abdominal Ultrasonography

    • Abdominal ultrasonography should be considered when suspecting hepatobiliary pathology.

    Chest CT Scan

    Abdominal CT Scan

    Positron Emission Tomography

    • PET may be useful in localizing the nidus of fever of unknown origin.

    Other Investigation

    Lymph Node Biopsy

    Bone Marrow Biopsy

    • Bone marrow biopsy may be considered when suspecting intracellular infectious pathogens or hematologic malignancies.

    Discontinuation of Nonessential Medications

    • Nonessential medications should be discontinued.
    • Defervescence in less than 72 hours after discontinuing the culprit medication suggests drug fever.
    • Rechallenge with the offending agent usually results in recurrence of drug fever.

    Trial of Empiric Antibiotics

    • Therapeutic trials of antimicrobial agents may be considered if other techniques fail to disclose the etiology.
    • An infectious etiology is likely if abatement of fever occurs after the administration of empiric antibiotics.

    Naproxen Test

    • Naproxen test (375 mg twice daily) can be used to distinguish neoplastic fever from other etiologies.
    • Naproxen test is considered positive when there is a rapid or sustained abatement of fever during the 3 days of the trial period.
    • Defervescence within 12 hours occurs in almost all patients with neoplastic fever.
    • Fever recurs after discontinuation of naproxen in patients with neoplasms.
    • Naproxen demonstrated no antipyretic activity against fever in patients with occult infection.


    • Management should be withheld until the etiology is ascertained so that treatment can be directed toward a specific pathology.
    • Empiric corticosteroids may be appropriate in patients with suspected temporal arteritis to prevent vascular complications.
    • Patients with febrile neutropenia should receive broad-spectrum antipseudomonal antibiotics immediately after specimens for cultures have been obtained.
    D/C nonessential Rx
    Defervescence in 72h
    Fever persists
    Drug fever
    CT or nuclear scan
    Focus identified
    Focus undetermined
    Verify with tissue biopsy
    IE suspected?
    Duke criteria fulfilled
    IE unlikely
    Treat as IE
    GCA suspected?
    GCA likely
    GCA unlikely
    Treat as GCA
    ANC < 500?
    Febrile neutropenia
    Normal ANC
    Antipseudomonal abx
    Follow up


    1. Arnow, P. M.; Flaherty, J. P. (1997-08-23). "Fever of unknown origin". Lancet. 350 (9077): 575–580. doi:10.1016/S0140-6736(97)07061-X. ISSN 0140-6736. PMID 9284789.
    2. Hirschmann, J. V. (1997-03). "Fever of unknown origin in adults". Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America. 24 (3): 291–300, quiz 301-302. ISSN 1058-4838. PMID 9114175. Check date values in: |date= (help)
    3. Chantada, G.; Casak, S.; Plata, J. D.; Pociecha, J.; Bologna, R. (1994-04). "Children with fever of unknown origin in Argentina: an analysis of 113 cases". The Pediatric Infectious Disease Journal. 13 (4): 260–263. ISSN 0891-3668. PMID 8036040. Check date values in: |date= (help)
    4. Zenone, Thierry (2006). "Fever of unknown origin in adults: evaluation of 144 cases in a non-university hospital". Scandinavian Journal of Infectious Diseases. 38 (8): 632–638. doi:10.1080/00365540600606564. ISSN 0036-5548. PMID 16857607.
    5. Iikuni, Y.; Okada, J.; Kondo, H.; Kashiwazaki, S. (1994-02). "Current fever of unknown origin 1982-1992". Internal Medicine (Tokyo, Japan). 33 (2): 67–73. ISSN 0918-2918. PMID 8019044. Check date values in: |date= (help)
    6. Isaac, Benedict (1991). Unexplained fever : a guide to the diagnosis and management of febrile states in medicine, surgery, pediatrics, and subspecialties. Boca Raton: CRC Press. ISBN 9780849345562.
    7. Cunha, B. A. (1996-03). "The clinical significance of fever patterns". Infectious Disease Clinics of North America. 10 (1): 33–44. ISSN 0891-5520. PMID 8698993. Check date values in: |date= (help)