Fever of unknown origin (FUO)

Type of disorder Common Uncommon Rare
Malignancy/neoplastic disorders Lymphomaa
Hypernephromas/renal cell carcinoma (RCC)
Pre-leukemias (AML)a
Myeloproliferative disorders (MPDs)
Atrial myxomas
Multiple myeloma
Colon carcinoma
Pancreatic carcinoma
CNS metastases
Liver metastases
Infectious diseases Miliary TB
Q fevera
Intra-abdominal/pelvic abscess
Intra/perinephric abscess
Typhoid fever/enteric feversa
Cat scratch disease (CSD)a
Extrapulmonary TB (renal TB, CNS TB)
Periapical dental abscess
Chronic sinusitis/mastoiditis
Subacute vertebral osteomyelitis
Aortoenteric fistula
Relapsing fevera
Rat-bite fevera
Visceral leishmaniasis (kala-azar)
Whipple’s diseasea
Castleman’s diseasea (MCD)
Rheumatologic/inflammatory disorders Adult Still’s diseasea
Giant cell arteritis
(GCA)/temporal arteritis (TA)a
Late-onset rheumatoid arthritis (LORA)a
Takayasu’s arteritisa
Kikuchi’s diseasea
Sarcoidosis (CNS)
Felty’s syndrome
Gaucher’s disease
Polyarticular gouta
Schnitzler’s syndromea
Behçet’s diseasea
FAPA syndromea
(Marshall’s syndrome)
Miscellaneous disorders Drug fevera
Alcoholic cirrhosisa
Subacute thyroiditisa
Regional enteritis (Crohn’s disease)a
Pulmonary emboli (small/multiple)
Kikuchi’s diseasea
Rosai–Dorman diseasea
Erdheim–Chester disease (ECD)a
Cyclic neutropeniaa
Familial periodic fever syndromesa

  • FMF
  • Hyper IgD syndromea
  • TNF receptor-1-

associated periodic
syndrome (TRAPS)

  • Muckle–Wells

Systemic mastocytosis
Hypothalamic dysfunction
Factitious fevera

a Also cause of recurrent FUOs.

Disorders with FUO potential include any not easily diagnosed disorder with prolonged fevers, travel-related infections with prolonged fevers presenting in nonendemic areas, any relapsing/recurrent disorder with prolonged fevers, or any disorder with prolonged fevers with unusual clinical findings.

Abbreviations: CNS = central nervous system; TB = tuberculosis; SBE = subacute bacterial endocarditis; CMV = cytomegalovirus; HIV = human immunodeficiency virus; EBV = Epstein–Barr virus; LGV = lymphogranuloma venereum; PAN = periarteritis nodosa; MPA = microscopic polyangiitis; SLE = systemic lupus erythematosus; FMF = familial Mediterranean fever; MCD = multicentric Castleman’s disease; FAPA = fever, aphthous ulcers, pharyngitis, adenitis; TNF = tumor necrosis factor; AML = acute myelogenous leukemia.

Adapted from: Cunha BA. Fever of unknown origin (FUO). In: Gorbach SL, Bartlett JB, Blacklow NR (Eds.) Infectious Diseases in Medicine and Surgery. (3rd edn.) Philadelphia: WB Saunders, 2004; pp. 1568–1577 and Cunha BA. Overview. In: Cunha BA (Ed.) Fever of Unknown Origin. New York: Informa Healthcare; 2007; pp. 1–16.

Diagnostic approach to FUOs

In patients presenting with prolonged fevers, the clinician should first determine if the patient indeed has an FUO. Because there are many causes of FUO, there is no “cookbook or algorithmic approach” for diagnosing FUOs. In medicine, the history provides important initial diagnostic clues and a general sense of the likely FUO category, e.g., weight loss with early anorexia suggests malignancy, arthralgias/myalgias suggest a rheumatic/inflammatory disorder, and fever with chills suggests an infectious etiology.

After an FUO category is suggested by historical clues, the physical examination should focus on history relevant findings in the differential diagnosis. The physical examination should not be comprehensive but more importantly should be carefully focused on demonstrating the presence or absence of key findings in the differential diagnosis, e.g., a complete neurologic exam is unhelpful in an FUO patient with probable adult Still’s disease. On physical examination particular attention should be given to eye findings, liver, spleen, lymph nodes, joint findings, and skin lesions (Table 1.2). At this point, based upon the presence or absence of history and physical examination clues, the initial FUO diagnostic workup, e.g., nonspecific laboratory tests, should also be focused on ruling in or ruling out the most likely diagnostic possibilities. Since the patient has already been seen by one or more physicians prior to presentation, routine laboratory tests have already been done, e.g., CBC, liver function test (LFTs), urinalysis (UA), but these tests should be carefully re-reviewed for diagnostic clues, e.g., relative lymphopenia.

Table 1.2 History and physical examination clues to fever of unknown origin (FUO) categories

Only gold members can continue reading. Log In or Register to continue

Jun 18, 2016 | Posted by in INFECTIOUS DISEASE | Comments Off on Fever of unknown origin (FUO)
Premium Wordpress Themes by UFO Themes
Historical features Clues from the history Physical examination findings Clues from the physical examination
Malignant/neoplastic disorders • PMH/FMH malignancy Possibility of same disease likely • Fever pattern:
• HA/mental confusion CNS metastases, lymphomas, multiple myeloma, atrial myxoma (CNS emboli) Relative bradycardia CNS, malignancies, lymphomas
Hectic/septic fevers (Pel-Ebstein) Lymphomas
• Weight loss (with early decreased appetite) Any malignant/neoplastic disorder • Cranial nerve palsies CNS lymphomas, CNS neoplasms
• Early satiety Lymphomas, any malignant/neoplastic disorder causing splenomegaly • Fundi: Roth spots Lymphomas, atrial myxoma
• Fundi: cytoid bodies (cotton wool spots) Atrial myxoma
• Pruritus (post hot shower/bath) Lymphoma, MPDs • Fundi: retinal hemorrhages Pre-leukemia (AML)
• Night sweats Any malignant/neoplastic disorder • Adenopathy Lymphoma, Kikuchi’s disease, Rosai–Dorfman disease
• Abdominal discomfort/pain Hypernephroma, hepatoma, liver metastases, colon carcinoma, pancreatic carcinoma • Sternal tenderness Pre-leukemia (AML), MPDs
• Heart murmur Marantic endocarditis, atrial myxoma
• Testicular pain Lymphoma • Hepatomegaly Hepatoma, hypernephroma, liver metastases
• Bone pain Multiple myeloma, any malignant/neoplastic disorder with bone involvement • Splenomegaly Lymphomas, MPDs
• Splinter hemorrhages Atrial myxoma
• Epididymitis Lymphomas
Infectious diseases • PMH/FMH of infections Possibility of same disease high • Fever pattern:
• HA/mental confusion Brucellosis, CSD, ehrlichiosis, Q fever, malaria, leptospirosis, Whipple’s disease, typhoid fever/enteric fevers, rat-bite fever, relapsing fever, CNS TB, HIV, LGV Relative bradycardia Typhoid fever/enteric fevers, leptospirosis, Q fever, malaria, babesiosis, ehrlichiosis
Double quotidian fever Visceral leishmaniasis (kala-azar)
Camelback fever curve Ehrlichiosis, leptospirosis, brucellosis, rat-bite fever (S. minus)
• Recent/similar illness exposure Possibility of same disease high Morning temperature spikes Miliary TB, typhoid fever/enteric fevers
• Surgical/invasive procedures Abscess, SBE
• Aortic aneurysm/repair Q fever, enteric fever Relapsing fevers Brucellosis, malaria, rat-bite fever (S. moniliformis)
• STD history LGV • Abducens (CN VI) palsy CNS TB
• Recent travel Typhoid/enteric fevers, leptospirosis, malaria, visceral leishmaniasis (kala-azar), brucellosis, Q fever • Conjunctival suffusion Trichinosis, relapsing fever, leptospirosis
• Conjunctival hemorrhages SBE
• Insect exposure Malaria, ehrlichiosis, babesiosis, visceral leishmaniasis (kala-azar), relapsing fever • Chorioretinitis Toxoplasmosis, TB, histoplasmosis
• Choroid tubercles Miliary TB
• Pet/animal contact Q fever, CSD, toxoplasmosis, rat-bite fever, relapsing fever, leptospirosis, brucellosis • Roth spots SBE
• Palatal petechiae EBV, CMV, toxoplasmosis
• Unpasteurized milk/cheese consumption Q fever, brucellosis • Tongue ulcer Histoplasmosis
• Adenopathy CSD, EBV, CMV
• Undercooked meat consumption Toxoplasmosis, trichinosis • Heart murmur SBE
• Spinal tenderness Subacute vertebral osteomyelitis, typhoid fever/enteric fever, skeletal TB, brucellosis
• Blood transfusions Malaria, babesiosis, ehrlichiosis, CMV, HIV • Hepatomegaly Q fever, typhoid fever/enteric fevers, brucellosis, visceral leishmaniasis (kala-azar), rat-bite fever, relapsing fever
• Poor dentition SBE, apical root abscess
• Sleep disturbances Brucellosis, relapsing fever, leptospirosis • Splenomegaly Miliary TB, EBV, CMV, typhoid fever/enteric fevers, brucellosis, histoplasmosis, ehrlichiosis, malaria, Q fever, SBE, CSD
Rat-bite fever, relapsing fever
• Early satiety EBV, CMV, Q fever, brucellosis, SBE, miliary TB
• Arthralgias Rat-bite fever, LGV, Whipple’s disease, brucellosis • Splinter hemorrhages SBE
• Ostler’s nodes/Janeway lesions SBE
• Myalgias Q fever, leptospirosis, relapsing fever, trichinosis • Skin hyperpigmentation Visceral leishmaniasis (kala-azar), Whipple’s disease
• Sinusitis Chronic sinusitis
• Night sweats Miliary TB, histoplasmosis • Epididymitis EBV, renal TB, brucellosis
• Weight loss Miliary TB, histoplasmosis
• Tongue pain Histoplasmosis, relapsing fever
• Neck pain Subacute vertebral osteomyelitis, chronic mastoiditis
• Tender finger tips SBE
• Abdominal pain Relapsing fever, leptospirosisv, typhoid fever/enteric fevers, trichinosis
• Back pain Subacute vertebral osteomyelitis, brucellosis, SBE
• Testicular pain EBV
Rheumatic/inflammatory disorders • PMH/FMH of rheumatic disorders Possibility of the same disease likely • Fever pattern:
• HA/mental confusion GCA/TA, CNS sarcoidosis, adult Still’s disease Double quotidian fever Adult Still’s disease
Morning temperature spikes PAN
• Transient facial edema Takayasu’s arteritis
• Hearing loss PAN • Lacrimal gland enlargement LORA, sarcoidosis, SLE
• Nasal stuffiness Sarcoidosis • Parotid gland enlargement Sarcoidosis
• Joint pain/swelling SLE, LORA, sarcoidosis, adult Still’s disease • Rash