Fever of Unknown Origin

Bryan Youree
Vanderbilt University Medical Center

Objectives
Definition and pathophysiology of
fever
FUO: classifications and etiology
Diagnostic workup of FUO
Prognosis

Fever versus Hyperthermia

Fever: resetting of the thermostatic setpoint in the 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

Mechanisms of Hyperthermia and

Associated Conditions
1. Excessive heat production: exertional
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

What is the normal human body

temperature?
A.
B.
C.
D.

37.5 C
98.6 F
340.15 K
Each human being is a unique individual,
and therefore, normal temperature
cannot be defined.

What is the normal human body

temperature?
A.
B.
C.
D.

37.6 C
98.6 F
340.15 K
Each human being is a unique individual,
and therefore, normal temperature
cannot be defined.

Wunderlichs Maxim
After analyzing >1 million axillary
temperatures from ~25,000 patients,
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.
Wunderlich C. Das Verhalten der Eiaenwarme in Krankenheiten.
Leipzig, Germany: Otto Wigard;1868.
2
Mackowiak, et al., JAMA 1992;268:1578
1

Normal Body Temperature

For healthy individuals 18 to 40 years of age,
the mean oral temperature is 36.8 0.4C
(98.2 0.7F)
Low levels occur at 6 A.M. and higher levels
at 4 to 6 P.M.
The maximum normal oral temperature is
37.2C (98.9F) at 6 A.M. and 37.7C
(99.9F) at 4 P.M.
These values define the 99th percentile for
healthy individuals.
Mackowiak, et al., JAMA 1992;268:1578

Normal Body Temperature Caveats

Rectal temperatures are generally 0.4C
(0.7F) higher than oral readings.
Tympanic membrane (TM) values are
0.8C (1.6F) lower than rectal
temperatures when thermometer is in the
unadjusted-mode.

How does fever occur?

A.
B.
C.
D.
E.
F.

Build up of evil humors

IL-1 and IL-6
TNF
Disruption of the medulla oblongata
A and D
B and C

How does fever occur?

A.
B.
C.
D.
E.
F.

Build up of evil humors

IL-1 and IL-6
TNF
Disruption of the medulla oblongata
A and D
B and C

Hypothetical Model for the Febrile Response

Interleukin-1 and TNF- 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.
Mackowiak, P. A. Arch Intern Med 1998;158:1870-1881.

Bacterial Pyrogens
Lipopolysaccharide (LPS) endotoxin
Endotoxin binds to LPS-binding protein and is transferred to CD14
on macrophages, which stimulates the release of TNF.

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, TNF and TNF,
and interferon (IFN)-gamma in large amounts

Group A and B streptococcal toxins

Exotoxins induce human mononuclear cells to synthesize not only
TNF but also IL1 and IL-6

Fever of Unknown Origin

(Historical Definition)
Fever of at least 3 weeks 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

Historical Causes of FUO

Hippocrates: excess of yellow bile
Middle Ages: demonic 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

Categories of FUO
Feature

Nosocomial

Neutropenic

HIV-associated

Classic

Patients
situation

Hospitalized,
acute care, no
infection when
admitted

Neutrophil count
Confirmed HIVeither <500/L or positive
expected to reach
that level in 1-2
days

All others with

fevers for 3
weeks

Duration of
illness while
investigated

3 daysb

3 daysb

3 daysb (or 4
weeks as
outpatient)

3 daysb or 3+
outpatient
visits

Examples

Septic
thrombophlebitis,
sinusitis, C.
difficile colitis,
drug fever

Perianal infection,
aspergillosis,
candidemia

MAIc infection,
TB, nonHodgkins
lymphoma, drug
fever

Infections,
malignancy,
inflammatory
diseases, drug
fever

All require temperatures of 38.3C (101F) on several occasions.

b
Includes at least 2 days incubation of microbiology cultures.
c
M. avium/M. intracellulare.
a

Modified from DT Durack, AC Street, in JS Remington, MN Swartz (eds):

Current Clinical Topics in Infectious Diseases. Cambridge, MA, Blackwell, 1991.

Etiology of FUO Over a 40 Year

Period

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

Infectious Causes of FUO

Intraabdominal abscess (liver, splenic, psoas,
etc)
Appendicitis, cholecystitis, 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

Infectious Causes of FUO

Intraabdominal abscess (liver, splenic, psoas,
etc)
Appendicitis, cholecystitis, 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

Infectious Causes of FUO

Intraabdominal abscess (liver, splenic, psoas,
etc)
Appendicitis, cholecystitis, 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

Infectious Causes of FUO

Intraabdominal abscess (liver, splenic, psoas,
etc)
Appendicitis, cholecystitis, 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

Infectious Causes of FUO

Tuberculosis, Mycobacterium avium complex,
syphilis, Q fever, legionellosis
Salmonellosis (including typhoid fever), listeriosis,
ehrlichiosis,
Actinomycosis, nocardiosis, Whipples 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

Collagen Vascular Diseases

Adult Stills disease, SLE
Giant cell arteritis/polymyalgia rheumatica,
ankylosing spondylitis
Wegeners granulomatosis
Rheumatic fever
Polymyositis, rheumatoid arthritis
Feltys syndrome, eosinophilic fasciitis

Malignancies
Lymphoma
Lymphoma
Lymphoma

Renal cell carcinoma

Hepatocellular carcinoma

Miscellaneous Causes of FUO

Complex partial status epilepticus,
cerebrovascular accident, brain tumour,
encephalitis
Drug fever, Sweets syndrome, familial
Mediterranean fever
Gout, pseudogout
Kawasakis syndrome, Kikuchis syndrome
Crohns disease, ulcerative colitis, sarcoidosis,
granulomatous hepatitis
Deep vein thrombosis
Atelectasis?

Drug Fever
No characteristic fever pattern
was observed.
Maximum temperatures
ranged from 38C to 43C
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.

Episodes
in Dallas
(n=51)
n
27/18
0
4

Episodes
in Lit.
(n=97)
n
53/44
3
12

Total
Episodes
(n=148)
%
56/44
2
11

Fever patterns reported

Continuous
Remittent
Intermittent
Hectic

51
0
19
6
26

41
9
7
13
12

62
10
28
21
41

Rigors
Relative bradycardia
Hypotension
Rash
Pruritus
Leukocytosis (>10K)
Eosinophilia (>300/mm3)
Hematologic
Deaths

26
5
6
20
11
11
21
1
2

52
4
21
6
0
0
12
12
4

53
11
18
18
7
7
22
9
4

Gender (male/female)
Hx of atopic disease
Previous hx of drug allergy

Mackowiak and LeMaistre Ann Intern Med 1987;106:728

Minimal Initial Diagnostic Workup

For FUO
Comprehensive history
Physical examination
CBC + differential
Blood 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

Liver Biopsy and Bone Marrow

Biopsy
Diagnostic yield of liver
biopsy 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

Volk et al. J Clin Pathol 1998;110:150

2
Riley et al. J Clin Pathol 1995:48:706
1

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

Diagnostic Value of Naproxen

77 patients presenting
with FUO were treated
with naproxen.
Overall temperature
decreased from
39.1C to 37.4C.
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

Proposed Approach to FUO

Mourad, O. et al. Arch Intern Med 2003;163:545-551.

Copyright restrictions may apply.

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

Approach to Fever in the ICU

Marik, P. E. Chest
2000;117:855-869

Prognosis
Prognosis is determined primarily by the
underlying disease.
Outcome is worst 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

Summary
FUO is often a diagnostic dilemma
Infections comprise ~30% of cases
Bone marrow biopsies are of low
diagnostic yield
Diagnostic approach should occur in a
step-wise fashion based on the H&P
Patients that remain undiagnosed
generally have a good prognosis