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Fever of Unknown Origin (FUO)

BASICS

  • Classic definition:
  • Fever >38.3°C
  • Duration ≥ 3 weeks
  • Uncertain diagnosis after ≥ 1 week inpatient workup
  • Causes categorized into infection, neoplasia, inflammatory, miscellaneous, undiagnosed
  • Often atypical presentation of common diseases; 75% resolve without diagnosis

EPIDEMIOLOGY

  • Incidence and prevalence unknown due to evolving diagnostics
  • Infectious causes more frequent in developing countries; noninfectious inflammatory causes more in developed countries

ETIOLOGY AND PATHOPHYSIOLOGY

Infectious Causes

  • Abdominal/pelvic abscesses, amebic hepatitis
  • Catheter infections
  • Cytomegalovirus
  • Endocarditis, pericarditis
  • HIV (advanced)
  • Mycobacterial infections (TB)
  • Osteomyelitis, pyelonephritis, sinusitis, wound infections

Neoplasms

  • Atrial myxoma
  • GI malignancies (colorectal, hepatoma)
  • Lymphoma, leukemia
  • Renal cell carcinoma

Noninfectious Inflammatory Diseases

  • Connective tissue diseases: Adult Still disease, RA, SLE
  • Granulomatous diseases: sarcoidosis, Crohn disease
  • Vasculitis: giant cell arteritis, polymyalgia rheumatica

Other Causes

  • Alcoholic hepatitis, cerebrovascular accident, cirrhosis
  • Drug-induced fever (multiple agents including allopurinol, hydralazine, isoniazid)
  • Endocrine disorders
  • Factitious fever
  • Occupational exposures, periodic fever syndromes
  • Pulmonary embolism/DVT
  • Thermoregulatory disorders

RISK FACTORS

  • Recent travel (malaria, tick-borne)
  • Biologic/chemical exposures
  • HIV infection (acute/advanced)
  • Elderly, drug abuse, immigrants
  • Young female healthcare workers (factitious)

GERIATRIC & PEDIATRIC CONSIDERATIONS

  • Geriatrics: more noninfectious inflammatory diseases, malignancies, drug fever
  • Pediatrics: 1/3 viral syndromes, 50% infectious, collagen vascular disease, malignancy common in older children

DIAGNOSIS

History

  • Fever onset, pattern
  • Constitutional symptoms: chills, night sweats, weight loss, arthralgia, fatigue
  • Past infections, surgeries, foreign materials
  • Medications including herbal supplements
  • Family history of periodic fever syndromes
  • Travel, occupational, sexual, recreational exposures

Physical Exam

  • Skin, eyes, lymph nodes, liver, spleen exam
  • Fundoscopy (Roth spots), temporal artery tenderness
  • Oral mucosa, cardiac, pulmonary, abdominal, rectal, testicular exams
  • Lymphadenopathy, nail changes, neurologic signs

Diagnostic Tests

Initial Tests

  • CBC, CRP, ESR, ANA, peripheral smear
  • Electrolytes, BUN, creatinine, LFTs, calcium, LDH, CPK
  • Serology: heterophile antibody, Hepatitis, RPR, HIV
  • Blood cultures (3 sets) before antibiotics
  • Urinalysis, urine culture
  • Chest X-ray, abdominal/pelvic CT or MRI

Follow-Up Tests

  • Rheumatoid factor, additional serologies (EBV, Lyme, Q fever, CMV, brucellosis, amebiasis, fungal infections)
  • Tuberculosis testing (TST, IGRA)
  • Thyroid function tests
  • Nuclear scans (technetium, FDG-PET/CT) for occult infections, tumors, inflammation
  • Echocardiography if suspect endocarditis or atrial myxoma
  • Doppler US for DVT/PE
  • Biopsies (liver, temporal artery, lymph node, bone marrow) as indicated
  • Lumbar puncture, endoscopy if indicated

TREATMENT

  • Etiology-specific treatment
  • Avoid empiric antibiotics unless neutropenic, immunocompromised, or critically ill
  • Therapeutic trials reserved for life-threatening or well-defined clinical scenarios (e.g., TB, temporal arteritis)
  • Antipyretics for symptom relief

ADMISSION

  • Ill, debilitated, or requiring invasive diagnostics
  • Consider if factitious fever suspected

ONGOING CARE

  • Repeat history, exam, and labs if diagnosis remains elusive

PATIENT EDUCATION

  • Maintain open communication; diagnostic process can be prolonged and frustrating

PROGNOSIS

  • Depends on underlying cause and patient factors
  • Spontaneous remission common in undiagnosed cases
  • Mortality higher in HIV patients
  • Survival rates: <35 yrs: 91%, 35-64 yrs: 82%, >64 yrs: 67%

COMPLICATIONS

  • Vary with etiology; risk increases with delayed diagnosis and treatment

REFERENCES

  1. Haidar G, Singh N. Fever of unknown origin. N Engl J Med. 2022;386(5):463-477.
  2. David A, Quinlan JD. Fever of unknown origin in adults. Am Fam Physician. 2022;105(2):137-143.
  3. Cunha BA, Lortholary O, Cunha CB. Fever of unknown origin: a clinical approach. Am J Med. 2015;128(10):1138.e1-1138.e15.

CODES

  • ICD10:
  • R50.9 Fever, unspecified

CLINICAL PEARLS

  • A thorough history and focused physical exam, combined with targeted investigations, is key to diagnosis.
  • Avoid indiscriminate empiric treatment; it can delay diagnosis.
  • FUO in elderly often reflects atypical presentations of common diseases.
  • Infectious causes dominate in developing countries; noninfectious inflammatory causes more common in developed countries.
  • Most FUO cases without diagnosis have favorable outcomes.