Fever of Unknown Origin

FUO
Prognosis

anterior hypothalamus and the resultant initiation of heat-conserving mechanisms until

the internal temperature reaches the new level.
Hyperthermia: an elevation in body temperature that occurs in the absence of resetting of the hypothalamic thermoregulatory center

hyperthermia, thyrotoxicosis, pheochromocytoma, cocaine, delerium tremens, malignant hyperthermia
2. Disorders of heat

dissipation: heat stroke, autonomic dysfunction
3. Disorders of hypothalamic function: neuroleptic malignant syndrome, CVA, trauma

human being is a unique individual, and therefore, normal temperature

cannot be defined.

human being is a unique individual, and therefore, normal temperature

cannot be defined.

Wunderlich identified 37.0° C (36.2-37.5) as the mean temperature in

healthy adults.
Temperature readings >38.0° C were deemed as “suspicious/probably febrile.”

1Wunderlich C. Das Verhalten der Eiaenwarme in Krankenheiten.
Leipzig, Germany: Otto Wigard;1868.
2Mackowiak, et al., JAMA 1992;268:1578

age, the mean oral temperature is 36.8° ± 0.4°C (98.2°

± 0.7°F)
Low levels occur at 6 A.M. and higher levels at 4 to 6 P.M.
The maximum normal oral temperature is 37.2°C (98.9°F) at 6 A.M. and 37.7°C (99.9°F) at 4 P.M.
These values define the 99th percentile for healthy individuals.

Mackowiak, et al., JAMA 1992;268:1578

than oral readings.
Tympanic membrane (TM) values are 0.8°C (1.6°F)

lower than rectal temperatures when thermometer is in the unadjusted-mode.

of the medulla oblongata
E. A and D
F. B and C

of the medulla oblongata
E. A and D
F. B and C

Febrile Response
Interleukin-1 β and TNF-α play prominent roles
in fever production

by stimulating the release of
cyclic AMP from the glial cells and activating
neuronal endings from the thermoregulatory
center that extend into the area.

transferred to CD14 on macrophages, which stimulates the release of

TNFα.
Staphylococcus aureus enterotoxins
Staphylococcus aureus toxic shock syndrome toxin (TSST)
Both Staphylococcus toxins are superantigens and activate T cells leading to the release of interleukin (IL)-1, IL-2, TNFα and TNFβ, and interferon (IFN)-gamma in large amounts
Group A and B streptococcal toxins
Exotoxins induce human mononuclear cells to synthesize not only TNFα but also IL1 and IL-6

duration
Temperature of 101° F (38.3° C) on several occasions
No diagnosis

after a 1 week evaluation in the hospital

Petersdorf and Beeson Medicine 1961;40:1

possession (encephalitis?)
18th Century: Friction associated with the flow of blood

through the vascular system and from fermentation and putrefaction occurring in the blood and intestines

least 2 days’ incubation of microbiology cultures.
cM. avium/M. intracellulare.
Modified from

DT Durack, AC Street, in JS Remington, MN Swartz (eds):
Current Clinical Topics in Infectious Diseases. Cambridge, MA, Blackwell, 1991.

Arch Intern Med. 2003;163:545

tubo-ovarian abscess, pyometra
Intracranial abscess, sinusitis, dental abscess
Chronic pharyngitis, tracheobronchitis, lung

abscess
Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection
Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis

tubo-ovarian abscess, pyometra
Intracranial abscess, sinusitis, dental abscess
Chronic pharyngitis, tracheobronchitis, lung

abscess
Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection
Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis

tubo-ovarian abscess, pyometra
Intracranial abscess, sinusitis, dental abscess
Chronic pharyngitis, tracheobronchitis, lung

abscess
Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection
Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis

tubo-ovarian abscess, pyometra
Intracranial abscess, sinusitis, dental abscess
Chronic pharyngitis, tracheobronchitis, lung

abscess
Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection
Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis

legionellosis
Salmonellosis (including typhoid fever), listeriosis, ehrlichiosis,
Actinomycosis, nocardiosis, Whipple’s disease
Fungal

(candidaemia, cryptococcosis, sporotrichosis, aspergillosis, mucormycosis, Malassezia furfur)
Malaria, babesiosis, toxoplasmosis, schistosomiasis, fascioliasis, toxocariasis, amoebiasis, infected hydatid cyst, trichinosis, trypanosomiasis
Cytomegalovirus, HIV, Herpes simplex, Epstein-Barr virus, parvovirus B19

spondylitis
Wegener’s granulomatosis
Rheumatic fever
Polymyositis, rheumatoid arthritis
Felty’s syndrome, eosinophilic fasciitis

tumour, encephalitis
Drug fever, Sweet’s syndrome, familial Mediterranean fever
Gout, pseudogout
Kawasaki’s syndrome,

Kikuchi’s syndrome
Crohn’s disease, ulcerative colitis, sarcoidosis, granulomatous hepatitis
Deep vein thrombosis
Atelectasis?

38°C to 43°C
The mean lag time between initiation of a

drug and the onset of fever was 21 days, but lag times varied considerably.
Alpha methyldopa and quinidine were the two drugs most commonly implicated, but antimicrobials (as a group) were responsible for the largest number of episodes.

Mackowiak and LeMaistre Ann Intern Med 1987;106:728

film reviewed by hematopathologist
Routine blood chemistry
UA and microscopy
Blood (x 3)

and urine cultures
Antinuclear antibodies, rheumatoid factor
HIV antibody
CMV IgM antibodies; heterophile antibody test (if c/w mono-like syndrome)
Q-fever serology (if risk factors)
Chest radiography
Hepatitis serology (if abnormal LFTs)

Mourad, et al. Arch Intern Med. 2003;163:545

has ranged from 14% to 17%.
Physical exam finding of hepatomegaly

or abnormal liver profile are not helpful in predicting abnormal biopsy result.
Complication rate is 0.06% to 0.32%

The diagnostic yield of bone marrow cultures in immunocompetent individuals has been found to be 0% to 2%1,2

Mourand et al. Arch Intern Med 2003;163:545

1Volk et al. J Clin Pathol 1998;110:150
2Riley et al. J Clin Pathol 1995:48:706

with naproxen.
Overall temperature decreased from 39.1°C to 37.4°C.
The sensitivity of

the naproxen test for neoplastive fever was 55% and the specificity was 62%.

Vanderschueren, et al. Am J Med 2003;115:572

2003;163:545-551.
Proposed Approach to FUO
Mourad, et al. Arch Intern Med. 2003;163:545

for neoplasms.
FUO patients who remain undiagnosed after extensive evaluation generally

have a favorable outcome and the fever usually resolves after 4-5 weeks.

Larson et al. Medicine 1982;61:269

marrow biopsies are of low diagnostic yield
Diagnostic approach should occur

in a step-wise fashion based on the H&P
Patient’s that remain undiagnosed generally have a good prognosis