Fever of Unknown Origin: A Clinical Approach

Significant weight loss (>2 lbs/week), particularly if accompanied by early anorexia, is a hallmark of malignant/neoplastic fevers of unknown origin.^{,  ,}  Post-hot bath pruritus suggests a malignant/neoplastic disorder.^{,  ,  ,}  A malignant/neoplastic fever of unknown origin should be considered in those with a history of adenopathy or malignancy.

The history should include prior/invasive procedures or surgeries (abscesses), dentition (apical abscesses, subacute bacterial endocarditis), antecedent/concomitant infections, and tuberculosis.^,  Animal or pet contact suggests Q fever, brucellosis, toxoplasmosis, cat scratch disease, or trichinosis.^{,  ,}  Mosquito or tick exposure suggests ehrlichiosis/anaplasmosis, babesiosis, or malaria, while rodent exposure suggests rat bite fever, relapsing fever, or leptospirosis.^{,  ,}  Blood transfusions may be an important clue to ehrlichiosis/anaplasmosis, babesiosis, cytomegalovirus, or human immunodeficiency virus. In normal hosts, the only clue to cytomegalovirus may be secretion exposure. Immunosuppressive drugs predispose to particular pathogens, for example, cytomegalovirus, tuberculosis. Disparate multiple symptoms/signs suggest multisystem disease, for example, miliary tuberculosis or Whipple's disease, rather than several different disorders.^, 

With prominent arthralgias/myalgias, a rheumatic/inflammatory fever of unknown origin is likely, but chills argue against a rheumatic/inflammatory etiology.^{,  ,}  Dry cough also may be a subtle clue of giant cell arteritis/temporal arteritis. With a fever of unknown origin, oral ulcers suggest Behçet's syndrome or systemic lupus erythematosus.^,  The pattern of organ involvement in a fever of unknown origin with a history of joint symptoms and generalized lymphadenopathy points to adult Still's disease or systemic lupus erythematosus.^,  A history of acalculous cholecystitis in a fever of unknown origin is an easily overlooked clue of systemic lupus erythematosus or periarteritis nodosa.^,  A family history is important if Behçet's disease is being considered.

If the history does not suggest a particular category, miscellaneous causes of fever of unknown origin should be considered. Fever periodicity may be the only clue to cyclic neutropenia. A history of lymphadenopathy may suggest Rosai-Dorfman or Kikuchi's disease.^,  Neck/jaw pain, easily dismissed as dental pain, may be a clue to subacute thyroiditis.^{,  ,  ,}  Factitious fever should be considered in medical personnel. Specifically, inquire about inflammatory bowel disease (regional enteritis), alcoholism (cirrhosis), and medications (pseudolymphoma, drug fever).^,  Some miscellaneous fevers of unknown origin are familial, for example, familial Mediterranean fever or hyper-IgD syndrome.^, 

Hectic fevers of lymphoma may resemble infection.^{,  ,}  Relative bradycardia may accompany lymphoma or central nervous system malignancy.^{,  ,}  Eye examination may be helpful, for example, Roth spots (lymphoma, atrial myxoma), cytoid bodies (atrial myxoma), or retinal hemorrhages (preleukemia).^,  A murmur is a key finding in subacute bacterial endocarditis, noninfectious culture-negative endocarditis, for example, marantic endocarditis or atrial myxoma.^,  Sternal tenderness points to a bone marrow disorder (preleukemia, myeloproliferative disorders).^{,  ,  ,}  Isolated hepatomegaly in a fever of unknown origin limits diagnostic possibilities to hepatoma, renal cell carcinoma, or liver metastases.^, 

The approach to infectious fevers of unknown origin begins with fever pattern analysis.^{,  ,  ,}  Morning temperature spikes suggest miliary tuberculosis, typhoid/enteric fever, or Whipple's disease.^{,  ,}  Relative bradycardia is a cardinal finding in typhoid/enteric fever, malaria, babesiosis, ehrlichiosis/anaplasmosis, leptospirosis, and Q fever.^,  Twice daily fever spikes (double quotidian fevers) suggest malaria, miliary tuberculosis, or visceral leishmaniasis.^,  Two fever peaks per week (camel back fever curve) may be one of the few clues to ehrlichiosis/anaplasmosis, leptospirosis, brucellosis, or rat bite fever.^{,  ,}  Fundoscopic findings may be a clue to toxoplasmosis, tuberculosis, histoplasmosis, or cat scratch disease. Spinal tenderness points to subacute vertebral osteomyelitis, typhoid/enteric fever, spinal tuberculosis, or brucellosis.^,  Hepatomegaly alone suggests Q fever, typhoid/enteric fever, visceral leishmaniasis, brucellosis, rat bite fever, or relapsing fever.^,  Splenomegaly narrows diagnostic possibilities to miliary tuberculosis, Epstein-Barr virus, cytomegalovirus, typhoid/enteric fever, brucellosis, histoplasmosis, ehrlichiosis/anaplasmosis, malaria, Q fever, subacute bacterial endocarditis, cat scratch disease, and rat bite fever.^,  Epididymo-orchitis/epididymal nodule is an easily overlooked sign of Epstein-Barr virus, renal tuberculosis, or brucellosis.^, 

Morning temperature spikes are an important clue to periarteritis nodosa while a double quotidian fever is a key finding in adult Still disease.^{,  ,  ,}  In a fever of unknown origin, rash, if present, suggests sarcoidosis, systemic lupus erythematosus, or adult Still's disease. Unequal pulse suggests Takayasu's arteritis. Lacrimal gland enlargement is a clue to late-onset rheumatoid arthritis, sarcoidosis, or systemic lupus erythematosus.^,  External eye/fundi may provide many diagnostic clues in rheumatic/inflammatory fevers of unknown origin, for example, cytoid bodies (systemic lupus erythematosus, giant cell arteritis/temporal arteritis, periarteritis nodosa, adult Still's disease), Roth spots (systemic lupus erythematosus, periarteritis nodosa), or retinal artery occlusion (Takayasu's arteritis, giant call arteritis/temporal arteritis, systemic lupus erythematosus).^{,  ,  ,  ,  ,}  In a fever of unknown origin, oral ulcers suggest Behçet's disease or systemic lupus erythematosus. Lymphadenopathy suggests systemic lupus erythematosus, late-onset rheumatoid arthritis, or sarcoidosis.^,  In a fever of unknown origin with systemic lupus erythematosus, a murmur with negative blood cultures suggests possible Libman-Sacks endocarditis. Hepatomegaly without splenomegaly argues against a rheumatic/inflammatory fever of unknown origin etiology. Epididymitis/epididymal nodules are subtle clues to periarteritis nodosa, systemic lupus erythematosus, or sarcoidosis.^{,  ,} 

Miscellaneous fevers of unknown origin are more likely to be diagnosed by historical clues rather than physical findings. Relative bradycardia is a clue to drug fever or factitious fever.^{,  ,}  Lipemia retinalis may be the only sign of hypertriglyceridemia. Lymphadenopathy may be due to pseudolymphoma or hyper-IgD syndrome.^,  Cirrhosis is an often-overlooked cause of fever of unknown origin. Splenomegaly is an important clue to regional enteritis, cirrhosis, or hyper-IgD syndrome.^,