Historical:  1907- Richard Cabot (MGH) described series of pts w/ long fevers, found 3 leading causes: 1) typhoid, 2) TB, 3) sepsis/endocarditis.  1961- Beeson, Petersdorf published prospective series, defined FUO: 1) illness > 3 wks, 2) fever > 101 on several occ, 3) no dx after 1 wk in hospital. 


Definition: Modified 2ndary to decreased hospitalization in modern era: 1) illness > 3 wks, 2) fever > 101 (38.3), 3) no dx after 1 wk intensive evaluation.


Etiologies:  The “Top Seven”(account for 50%)- TB, endocarditis, lymphoma, solid tumor, Still’s, vasculitis, common rheumatologic disorder. 


1.   Infection (30-40%)


a.            endocarditis

b.            intrabdominal infection- hepatic, diverticular, splenic, subphrenic, pancreatic, biliary, psoas, pelvic

c.   UTI- pyelo, perinephric, prostatic

d.            osteomyelitis

e.   URI- dental abcess, sinusitis

f.    infected peripheral vessels

Generalized- bacterial, MTB, fungus, viral (CMV!), parasitic

1.   Neoplasia (20-30%)

a.            lymphoproliferative- lymphoma most common (Pel-Ebstein fever)

b.            leukemia- AML

c.   MDS

d.   solid tumors- RCCa most common, atrial myxoma

1.      Rheumatologic (10-20%)

a.   adult Still’s disease

b.   giant-cell arteritis, PMR- exclusively > 50y

c.   other vasculitis- Wegner’s, Takayasu’s, PAN, cryoglobulinemia

d.   other rheum- SLE, RA, Sjogren’s

1.      Miscellaneous (15-20%)

a.            granulomatous- Crohn’s, sarcoid

b.   EtOH hepatitis- AST:ALT > 2:1, <600

c.            vascular- PE, hematoma

d.   drug- almost always remits w/in 72h of stopping

e.            hereditary- FMF(recurrent fever, peritonitis, leukocytosis)

f.            endocrine- hyperthyroid, subacute thyroiditis, adrenal insufficiency

g.            factitious

1.   No dx (5-15%): prognosis GOOD



Diagnostic workup:

1.   History

a.   focus on: prior medical problems, surgeries, travel, exposure to animals and TB, PPD

b.   pattern and height of fever, chills, sweats, bradycardia NOT generally helpful

1.   Physical exam

a.   eyes- sclera, conjunctivae, dilated fundus exam

b.   nodes

c.   skin and mucous membranes- rash, petechiae, Osler/Janeway, ulcers

1.      Labs/imaging

a.   initial- CBC, UA/Cx, SMA7, LFTs, BCx(3 in 24hrs), CXR

b.   further studies (individually tailored)- AbdCT, BM Bx, Liver Bx, TA Bx, ChestCT, ESR, ANA, RF, ACE, CMV, PPD, HIV


General prinicples:

1.   Horses and zebras

2.   Sutton’s Law

3.   Back to the drawing board


Hirschman. Clin Inf Dis. 1997; 24: 291-302