Differential Overview

Infection
  • HIV
  • Tuberculosis
  • Endocarditis
  • Osteomyelitis
  • Malaria
  • Syphilis
  • Zoonosis
  • Typhoid fever
  • Chronic meningococcemia
Neoplasm
  • Lymphoma
  • Liver metastases
  • Renal cell carcinoma
  • Atrial myxoma
Collagen-Vascular Disease
  • Giant cell arteritis
  • Systemic lupus erythematosus
  • Vasculitis
  • Rheumatic fever
  • Still disease
Other
  • Drugs
  • Heat stroke
  • Factitious
  • Malignant hyperthermia
  • Multiple pulmonary emboli
Fever of unknown origin (FUO), when a fever over 101°F (38.5°C) remains unexplained for longer than 3 weeks, is usually a result of infection (40%), neoplasm (20%), or collagen-vascular disease (20%). It is most commonly caused by an atypical presentation of a common disease. Always document the fever before pursuing the evaluation.
Consider relatively hidden (deep) sites: retroperitoneum (hematoma or infection), bone, dental, sinus, ovary, prostate, subphrenic (following abdominal surgery), renal, spleen, or prostheses. With FUO in a hospitalized patient, consider sequestered sites (e.g., sinuses in intubated patients or implanted hardware), indwelling lines, C. difficile, or drug reactions. With FUO in a neutropenic patient, consider catheters, perianal infections, Candida, and Aspergillus. Cardinal signs may be absent, e.g., meningitis with opportunistic pathogens without meningismus in 63%, and pneumonia without purulent sputum in 92%. Neutropenic fevers are usually due to bacteremia, with fungal organisms becoming predominant after 7 days of unremitting fever. Fever may also be due to the underlying neoplasm, drugs such as antibiotics, or blood products.

Examine for subtle clues:
  • Petechial eruptions in meningococcemia and Rocky Mountain Spotted Fever
  • Pustular lesions in gonococcemia or staphylococcal sepsis
  • Ecthyma gangrenosum in Pseudomonas sepsis
  • Splinter hemorrhages, conjunctival hemorrhages, Roth spots, Osler nodes, and Janeway lesions in endocarditis
  • Choroidal tubercles in miliary tuberculosis and candidemia
  • Splenomegaly in endocarditis, lymphoma, and cirrhosis
  • Hepatic bruit or friction rub in subphrenic abscess
  • Temporal artery or scalp tenderness or jaw claudication in giant cell arteritis
  • Epitrochlear lymphadenopathy in syphilis
Extreme elevations of fever (>40°C) are found in heat stroke, hypothalamic dysfunction, meningitis, midbrain hemorrhage, falciparum malaria, Rocky Mountain Spotted Fever, typhus, sepsis, malignant hyperthermia, and hypernephroma.
Relative bradycardia occurs in salmonellosis (typhoid fever), meningitis with increased intracranial pressure, mycoplasma and legionella pneumonia, factitious fever, tularemia, brucellosis, mumps, hepatitis, and with concomitant beta blockers. Bradycardia in fever may also signal cardiac conduction abnormalities in acute rheumatic fever, Lyme disease, viral myocarditis, or endocarditis with valve ring abscess.
Relapsing fevers (days of fever alternating with days without) occur in brucellosis (fever with physical activity), Hodgkin disease, extrapulmonary tuberculosis, malaria, and Lyme disease. Hectic fever (difference between peak and trough >1.5°C) suggests abscess, pyelonephritis, ascending cholangitis, tuberculosis, lymphoma, and drug reactions. Absence of diurnal variation suggests a central source. Reversal of the diurnal pattern (“typhus inversus”) occurs with disseminated tuberculosis, typhoid fever, polyarteritis nodosa, and salicylate toxicity.
FUO in patients from the developing world include tuberculosis, typhoid, amebic liver abscesses, AIDS, and geographically restricted infections such as malaria, schistosomiasis, brucellosis, kala azar, filariasis, or Lassa fever. They may present after long incubation or latency periods.

When FUO lasts longer than 6 months, consider factitious fever, granulomatous hepatitis, neoplasm, Still disease, infection, collagen-vascular disease, or exaggerated circadian rhythm.