Fever of Unknown Origin

“The mark of a good ID clinician is not how many antibiotics he or she starts but how many he or she stops.” — Brad Cutrell

Definitions

  • “Classic” definition of FUO
    • Fever > 38.3 C
    • Duration > 3 weeks
    • Unknown etiology after > 1 week hospital evaluation
  • Revised Classification: proposed revisions decreased duration and removed inpt evaluation criteria
    • šClassic Definition: temperature higher than 38.0 °C (100.4 °F) for more than 3 weeks and either more than 3 days of hospital investigation or more than two outpatient visits without determination of the cause.š
    • Health care–associated FUO: temperature higher than 38.0 °C (100.4 °F) for more than 3 days in a hospitalized patient receiving acute care with infection not present or incubating on admission.
    • šImmune-deficient (neutropenic) FUO: štemperature higher than 38.0 °C (100.4 °F) in a patient in with ANC < 500 in whom the diagnosis remains uncertain after more than 3 days despite appropriate investigation, including at least 48 hours’ incubation of microbiologic cultures.
    • šHIV-related FUO: temperature higher than 38.0 °C (100.4 °F) in a patient with confirmed HIV infection for more than 3 weeks in outpatients or more than 3 days in inpatients.

Epidemiology

  • Classic FUO etiologies fall into 5 major categories: Infection, Malignancy, Inflammatory, Miscellaneous, Unknown
  • Distribution depends on decade, patient age, geography, and type of practice
  • Classic FUO Epid
  • Classic FUO Epi Trends

Etiology

  • Infections
    • Tuberculosis (extrapulmonary, miliary, IC hosts)
    • Occult abscess (abd/pelvic)
    • Complicated UTI
    • Osteomyelitis
    • Culture-negative endocarditis
    • Malaria
    • Typhoid fever
    • Visceral Leishmaniasis
  • Malignancies
    • Lymphoma (esp. NHL)
    • Leukemia
    • Renal Cell carcinoma
    • Hepatocellular carcinoma or liver metastases
  • Inflammatory Disorders
    • Adult-onset Still’s Disease
    • RA
    • SLE
    • Temporal arteritis (Giant Cell arteritis)
    • Polymyalgia rheumatica
  • Miscellaneous
    • Drug Fever (abx, anti-seizure meds, NSAIDs, anti-arrhythmics)
    • Alcoholic hepatitis
    • Venous thromboembolic disease
    • Endocrine disease (hyperT, adrenal insufficiency, pheo)
    • Disordered heat homeostasis (“central fever”)
    • Factitious Fever (Munchausen)
  • Special Populations
    •  Pediatrics
      • Infectious most often, particularly viral and respiratory
      • CTD: Kawasaki in younger, AOSD in older children
    •  Geriatrics
      • CTD (GCA and PMR) and malignancy more common than in < 65 age group
    • Returning Traveler
      • Malaria, typhoid fever, amebic liver abscess, acute HIV

Diagnostic Evaluation

  • History and Physical!
    • Recent prospective Dutch series found average of 10.5 potential diagnostic clues per pt from history/exam and only 3 per pt from lab testing (81% misleading)
    • Dx
  • Laboratory Testing
    • Best guided by history/exam clues, not “shotgun” approach
    • Laboratory testing yields diagnosis in 25% of cases
    • Labs
  •  Imaging
    • CXR and CT abdomen/pelvis part of initial tests
    • MRI/MRA good for CNS, spine, and vasculitis evaluation
    • Older nuclear tagged scans and Gallium scans have been largely replaced by FDG-PET scans
    • Recent meta-analysis showed pooled sens. 98% and spec. 86% for FDG-PET, arguing for role if initial w/u negative
  • Invasive Testing
    • BM evaluation useful, especially if abnormal CBC or immunocompromised host
    • Biopsy of sites with suspected involvement in select cases

Management and Prognosis

  • Management
    • Therapeutic trials of abx generally not recommended
    • “Non-specific Rx rarely cures FUO but may delay Dx.”
    • Exceptions: empiric steroids for suspected GCA or empiric abx in neutropenic patients
  • Prognosis
    • Depends on age and etiology of FUO (worse with elderly and malignancy as etiology)
    • Most without Dx after extensive evaluation have good prognosis with low mortality and fever resolution
  • Remember: The cause is more likely a common diagnosis presenting in an atypical fashion than a rare disease presenting in a typical fashion.
  • FTMO

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