> Table of Contents > Fever of Unknown Origin (FUO)
Fever of Unknown Origin (FUO)
Scott T. Henderson, MD
image BASICS
DESCRIPTION
  • Classic definition
    • Repeated fever >38.3°C
    • Fever duration at least 3 weeks
    • Uncertain diagnosis after 1 week of study in the hospital
  • The FUO definition has evolved over time and should be based on characteristics and patient subtypes. In-hospital evaluation has been eliminated in previously healthy people.
  • Some expand the definition to include nosocomial, neutropenic, and shorter duration HIV-associated fevers.
EPIDEMIOLOGY
Incidence
Incidence unclear
ETIOLOGY AND PATHOPHYSIOLOGY
  • >200 causes; each with prevalence of ≤5%
  • Most commonly, FUO is an atypical presentation of a common condition.
  • Spectrum of causes varies by geography
  • Infection
    • Abdominal or pelvic abscesses
    • Amebic hepatitis
    • Catheter infections
    • Cytomegalovirus
    • Dental abscesses
    • Endocarditis/pericarditis
    • HIV (advanced stage)
    • Mycobacterial infection (often with advanced HIV)
    • Osteomyelitis
    • Renal
    • Sinusitis
    • Wound infections
    • Other miscellaneous infections
  • Neoplasms
    • Atrial myxoma
    • Colorectal cancer
    • Hepatoma
    • Lymphoma
    • Leukemia
    • Solid tumors (renal cell carcinoma)
  • Noninfectious inflammatory disease
    • Connective tissue diseases
      • Adult Still disease
      • Rheumatoid arthritis
      • Systemic lupus erythematosus
    • Granulomatous disease
      • Crohn disease
      • Sarcoidosis
    • Vasculitis syndromes
      • Giant cell arteritis
      • Polymyalgia rheumatica
  • Other causes
    • Alcoholic hepatitis
    • Cerebrovascular accident
    • Cirrhosis
    • Medications
      • Allopurinol, captopril, carbamazepine, cephalosporins, cimetidine, clofibrate, erythromycin, heparin, hydralazine, hydrochlorothiazide, isoniazid, meperidine, methyldopa, nifedipine, nitrofurantoin, penicillin, phenytoin, procainamide, quinidine, sulfonamides
    • Endocrine disease
    • Factitious/fraudulent fever
    • Occupational causes
    • Periodic fever
    • Pulmonary emboli/deep vein thrombosis
    • Thermoregulatory disorders
  • In up to 20-30% of cases, the cause of the fever will not be identified despite thorough workup.
RISK FACTORS
  • Recent travel
  • Exposure to biologic or chemical agents
  • HIV-infection (particularly in advanced stages)
  • Elderly
  • Drug abuse
  • Immigrants
  • Young female health care workers (consider factitious fever)
Geriatric Considerations
Noninfectious inflammatory diseases are the most frequent causes in high-income countries. This most commonly includes temporal arteritis, polymyalgia rheumatica, or rheumatoid arthritis. In elderly patients with infections, common causes include intra-abdominal abscess, complicated urinary tract infection, tuberculosis, and endocarditis. Other common causes of FUO in patients >65 years include malignancies, particularly hematologic malignancies and drug-induced fever.
Pediatric Considerations
  • ˜50% of FUO in published pediatric case series are infectious. Collagen vascular disease, malignancy are also common (1)[A].
  • Inflammatory bowel is a common cause in older children and adolescents.
image DIAGNOSIS
PHYSICAL EXAM
  • Physical findings with high diagnostic yield
    • Funduscopic exam for choroid tubercles or Roth spots
    • Temporal artery tenderness
    • Oral-mucosal lesions
    • Auscultation for bruits and murmurs
    • Abdominal palpation for organomegaly
    • Rectal examination
    • Testicular examination
    • Lymph node examination
    • Skin and nail bed exam for clubbing, nodules, lesions, and erosions
    • Focal neurologic signs
    • Bony tenderness or joint effusion
    • Serial exams are often helpful for evolving physical signs associated with FUO (e.g., lesions associated with endocarditis).
DIFFERENTIAL DIAGNOSIS
See “Etiology and Pathophysiology.”
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • CBC
  • Peripheral blood smear
  • Electrolytes, BUN and creatinine
  • Lactate dehydrogenase
  • Calcium
  • LFTs
  • C-reactive protein, ESR
  • HIV testing
  • Blood cultures (not to exceed six sets)
  • Urinalysis and urine culture
  • Chest x-ray
  • CT or MRI of abdomen and pelvis (with directed biopsy, if indicated) (2)[C]
Follow-Up Tests & Special Considerations
  • Rheumatoid factor and antinuclear antibody test
  • Serologic tests: Epstein-Barr, hepatitis, syphilis, Lyme disease, Q fever, cytomegalovirus, amebiasis, coccidioidomycosis
  • Serum ferritin
  • Serum protein electrophoresis
  • Sputum and urine cultures for TB
  • Thyroid function tests
  • Tuberculin skin test
    • May not be helpful if anergic or acute infection
    • If test negative, repeat in 2 weeks
    • If indicated, consider an interferon gamma release assay (IGRA) test.
  • Technetium-based scan, if infectious process or tumor suspected (2)[B]
  • FDG-PET/CT scan if infectious process, inflammatory process, or tumor suspected; PET scans have a high negative predictive value and good sensitivity (but may have false positives) (3)[A].
  • P.377

  • Ultrasound of abdomen and pelvis (plus directed biopsy, if indicated) if renal obstruction or gallbladder/biliary tree pathology suspected
  • Echocardiogram if cardiac valve lesions (endocarditis), atrial myxomas, or pericardial effusion is suspected
  • Lower-extremity Doppler if deep vein thrombosis/pulmonary embolism suspected
  • CT scan of chest if pulmonary emboli suspected
  • Indium-labeled leukocyte scanning if inflammatory process or occult abscess suspected
  • Bone scan if osteomyelitis or metastatic disease suspected
Diagnostic Procedures/Other
  • Liver biopsy if granulomatous disease suspected (2)[C]
  • Temporal artery biopsy, particularly in the elderly
  • Lymph node, muscle, or skin biopsy, if clinically indicated
  • Bone marrow aspiration biopsy with smear, culture, histologic examination, and flow cytometry
  • Spinal tap, if clinically indicated
Test Interpretation
Depends on etiology
image TREATMENT
GENERAL MEASURES
  • Treatment depends on the specific etiology.
  • Therapeutic trials are a last resort and should be as specific as possible based on available clinical evidence. Such “shotgun” approaches are discouraged because they obscure the clinical picture, have untoward effects, and do not provide a diagnostic solution (2)[C].
MEDICATION
First Line
  • First-line drugs depend on the diagnosis.
  • Evidence does not support isolated treatment of fever (4)[C].
Second Line
Only if the patient has localizing symptoms associated with the fever or continues to decline, consider a therapeutic trial—consultation with appropriate specialists (infectious disease, rheumatology) is recommended in this case.
  • Antibiotic trial based on patient's history and suspected culture negative endocarditis
  • Antituberculous therapy if there is a high risk for TB pending definitive culture results
  • Corticosteroid trial based on patient's history (once occult malignancy is ruled out) if temporal arteritis is suspected
ADDITIONAL THERAPIES
Febrile patients have increased caloric and fluid demands.
SURGERY/OTHER PROCEDURES
The need for exploratory laparotomy has been largely eliminated with the advent of more sophisticated tests and imaging modalities.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
  • Reserved for the ill and debilitated
  • Consider if factitious fever has been ruled out or an invasive procedure is indicated
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
If the etiology of the fever remains unknown, repeat the history, physical exam, and screening lab studies.
DIET
No specific dietary recommendations have been shown to ameliorate undiagnosed fever.
PATIENT EDUCATION
Maintain an open line of communication between physician and patient/family as the workup progresses:
  • The extended time required in establishing a diagnosis can be frustrating.
PROGNOSIS
  • Depends on etiology and age
  • Patients with HIV have the highest mortality.
  • 1-year survival rates (reflecting deaths due to all causes)

Age

Survival

<35 years

91%

35-64 years

82%

>64 years

67%

REFERENCES
1. Chow A, Robinson JL. Fever of unknown origin in children: a systematic review. World J Pediatr. 2011;7(1):5-10.
2. Mourad O, Palda V, Detsky AS. A comprehensive evidence-based approach to fever of unknown origin. Arch Intern Med. 2003;163(5):545-551.
3. Hao R, Yuan L, Kan Y, et al. Diagnostic performance of 18F-FDG PET/CT in patients with fever of unknown origin: a meta-analysis. Nucl Med Commun. 2013;34(7):682-688.
4. Hersch EC, Oh RC. Prolonged febrile illness and fever of unknown origin in adults. Am Fam Physician. 2014;90(2):91-96.
Additional Reading
&NA;
  • Ben-Baruch S, Canaani J, Braunstein R, et al. Predictive parameters for a diagnostic bone marrow biopsy specimen in the work-up of fever of unknown origin. Mayo Clin Proc. 2012;87(2):136-142.
  • Hayakawa K, Ramasamy B, Chandrasekar PH. Fever of unknown origin: an evidence-based review. Am J Med Sci. 2012;344(4):307-316.
  • Varghese GM, Trowbridge P, Doherty T. Investigating and managing pyrexia of unknown origin in adults. BMJ. 2010;341:C5470.
See Also
&NA;
  • Arthritis, Juvenile Idiopathic; Colorectal Cancer; Cytomegalovirus (CMV) Inclusion Disease; Endocarditis, Infective; Hepatoma; HIV/AIDS; Lupus Erythematosus, Discoid; Osteomyelitis; Polyarteritis Nodosa; Polymyalgia Rheumatica; Pulmonary Embolism; Rheumatic Fever; Sinusitis; Stroke, Acute; Arteritis, Temporal
  • Algorithms: Fever in the First 3 Months of Life; Fever of Unknown Origin
Codes
&NA;
ICD10
R50.9 Fever, unspecified
Clinical Pearls
&NA;
  • A sequential approach to FUO based on a careful history, physical examination, and targeted testing/imaging typically leads to a rational diagnosis in most cases.
  • Use empiric therapy only in carefully defined circumstances.
  • FUO cases that defy precise diagnosis after intensive investigation and prolonged observation generally carry a favorable prognosis.
  • FUO in older persons may represent an atypical presentations of a common disease.
  • The most common causes of FUO in high-income countries are noninfectous inflammatory diseases and cases that remain idiopathic.