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.
Wunderlich’s 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.”
1Wunderlich
C. Das Verhalten der Eiaenwarme in Krankenheiten.
Leipzig, Germany: Otto Wigard;1868.
2Mackowiak, et al., JAMA 1992;268:1578
Normal Body Temperature
For healthy individuals 18 to 40 years of 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
Normal Body Temperature Caveats
Rectal temperatures are generally 0.4°C
(0.7°F) higher 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.
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 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.
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 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
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
Patient’s
situation
Hospitalized,
acute care, no
infection when
admitted
Neutrophil count
Confirmed HIVeither <500/µL 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 3+
outpatient
visits
Examples
Septic
thrombophlebitis,
sinusitis, C.
difficile colitis,
drug fever
Perianal infection, MAIc infection,
aspergillosis,
TB, noncandidemia
Hodgkin’s
lymphoma, drug
fever
3 daysb (or 4
weeks as
outpatient)
Infections,
malignancy,
inflammatory
diseases, drug
fever
require temperatures of ≥38.3°C (101°F) on several occasions.
bIncludes at least 2 days’ incubation of microbiology cultures.
cM. avium/M. intracellulare.
aAll
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, 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
Collagen Vascular Diseases
Adult Still’s disease, SLE
Giant cell arteritis/polymyalgia rheumatica,
ankylosing spondylitis
Wegener’s granulomatosis
Rheumatic fever
Polymyositis, rheumatoid arthritis
Felty’s 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, 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?
Drug Fever
No characteristic fever
pattern was observed.
Maximum temperatures
ranged from 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.
Gender (male/female)
Hx of atopic disease
Previous hx of drug allergy
Fever patterns reported
Continuous
Remittent
Intermittent
Hectic
Rigors
Relative bradycardia
Hypotension
Rash
Pruritus
Leukocytosis (>10K)
Eosinophilia (>300/mm3)
Hematologic
Deaths
Episodes
in Dallas
(n=51)
n
27/18
0
4
51
0
19
6
26
26
5
6
20
11
11
21
1
2
Episodes
in Lit.
(n=97)
n
53/44
3
12
41
9
7
13
12
52
4
21
6
0
0
12
12
4
Total
Episodes
(n=148)
%
56/44
2
11
62
10
28
21
41
53
11
18
18
7
7
22
9
4
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
1Volk
et al. J Clin Pathol 1998;110:150
2Riley et al. J Clin Pathol 1995:48:706
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
39.1°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
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
Patient’s that remain undiagnosed
generally have a good prognosis