Fever of Unknown Origin

Fever of Unknown Origin
AIMGP Seminar Series

Dr. Katina Tzanetos
February 2007
References
Mourad,
O., et al. A Comprehensive EvidencedBased Approach to Fever of Unknown Origin.

Arch Inter Med 163: March 10, 2003.
Roth, A. and Basello, G. Approach to the Adult
Patient with Fever of Unknown Origin. American
Family Physician 68 (11), 2223.
Up To Date.
Approach to the adult with fever of unknown origin
Etiologies of fever of unknown origin in adults
* Much of this talk based on very helpful
article by Mourad et al. Highly recommended
Case Discussion Based on Real Patient

28-year
old female, born in Canada, parents from

Hong Kong
2.5 week history of fever 40.0C or higher
Only other symptom is possible rash on lower legs
intermittent, tender, red nodules
Works in bank
Non-smoker, non-drinker
Only medication is OCP
Take a minute to discuss

Does
she fit the criteria for Fever of

Unknown Origin
Why
or why not?
Fever of Unknown Origin - Definition

Classic
definition
Temperature higher than 38.3C

Several occasions
Cause obscure after 1-week of in-patient
evaluation
Current
definition
recognizes acceptability of out-patient in place
of in-patient investigations
Case Discussion
Based
on short duration and absence of

investigations patient does not fit diagnostic
criteria
If fever persists, should pursue diagnosis
Her fever persists
What aspects of the history and physical
examination do you focus on during this initial

visit?
Four Proposed Categories of FUO

Based
on potential etiology of FUO

All require temperature > 38.3C
Categorization be especially helpful in organizing
an approach to patient evaluation
Classic
Nosocomial
Immune-deficient (neutropenic)
HIV-related
Classic Category of FUO

Definition:
Duration > 3 weeks, evaluation of at least 3
outpatient visits or 3 days in-hospital

Common
etiologies:
Infection, malignancy, CVD
This category will be the focus of this talk
Nosocomial Category of FUO

Definition:
Hospitalization of at least 24 hrs with no fever
on admission, evaluation of at least 3 days

Common
etiologies:
C.Difficile, drugs, PE, septic thrombophlebitis,
sinusitis (intubated patients)
Immune-deficient (neutropenic)
Category of FUO
Definition:
Neutrophil count < 500/mm3, evaluation of at
least 3 days
Etiologies:
Opportunistic bacterial infections, aspergillosis,
candidiasis, herpes virus
HIV-Associated Category of FUO

Definition:
Duration of at least 4 weeks for outpatients and
3 days for inpatients, HIV confirmed

Etiologies:
Cytomegalovirus, MAI, Pneumocystis, drugs,
Kaposis, lymphoma
Etiology and Epidemiology

of Classic FUO
Infections: Most common cause accounting for 1/3 of cases

TB; Most common infection in non-elderly adults
PPD positive in less than 50% of pts with TB and FUO, Sputum
samples positive in only of patients
Abscesses
Usually in abdomen or pelvis with some pre-disposing cause (e.g. recent
surgery, diabetes, biliary tract disease, recent UTI)
Other infections: Osteomyelitis, endocarditis (esp. in pts with recent antibiotic
use or HACEK organisms)
Malignancy: Second most common cause

Lymphoma (esp. non-Hodgkins), Leukemia, Renal cell, HCC, other
metastasis to liver
CVD: Third most common cause

Adult Stills disease in younger patients and giant cell arteritis in older
patients
Diagnostic Approach - History

History
Travel
Exposures to toxins, sick persons, animals
Immunosuppression
Localizing symptoms
Look for subtle findings: eg. Jaw claudication, nocturia
with prostatitis
Degree
of fever, nature of fever curve, apparent

toxicity, and response to antipyretics not specific
enough to guide management
Diagnostic Approach
Physical Examination
Repeated
examination may be needed

Careful attention to skin, mucous
membranes, lymph and abdominal system
Ask pts to record and measure temperature
daily
Yield from history and physical
examination unknown
Back to the case

Thorough
history and physical noncontributory except for intermittent skin

lesions
Given
what you know thus far, what

investigations would you order?
Diagnostic Approach
Laboratory Investigations
Suggested minimal diagnostic work-up to qualify as FUO has

varied over the years
Recent article by Mourad et al suggests following as minimal:
History and physical examination

CBC and differential
Blood film reviewed by hematopathologist
Routine chemistry including LDH, bilirubin, liver enzymes
Urinalysis and microscopy
ANA, RH factor
HIV
CMV IgM; heterophil test if suspicious for Mononucleosis
Q-fever serology (if risk exists)
CXR
Hepatitis serology (if abnormal liver enzymes)
Diagnostic Approach
Investigations and the Evidence
Abdominal
CT
Useful to look for abdominal lymphoma and
abscess
Diagnostic yield in case series 19%
Clinical follow-up showed that only 1/32
patients with normal scans had an intraabdominal cause for FUO
Diagnostic Approach
Nuclear
Imaging:
For localizing inflammatory or infectious focus
Technetium scans likely have best test
characteristics overall and should be test of
choice
Technetium studies: specificity 93%, sensitivity 4075%; PLR 5.7-12.5
Indium-labeled WBC scans: specificity 69%-86%,
sensitivity 45%-82%
Gallium scans: (limited studies)
Diagnostic Approach
Duke criteria for endocarditis:
Endocardities: 1-5% of all cases of FUO
Sensitivity 82%, specificity 99%
Liver Biopsy:
Diagnostic yield 14%-17% regardless of whether
abnormal physical exam or liver enzymes exist

Complications in FUO from biopsy only 0.32% at most
Recommended
Diagnostic Approach
Temporal artery biopsy
Large studies comprised of elderly with FUO lacking
Arteritis cause of FUO ~16% of pts (All comers)
Safe, recommended in elderly with FUO
Leg dopplers
DVT cause of FUO ~ 2-6% of pts
Safe, easy to do, recommended
Diagnostic Approach
Bone
Marrow Examination
Diagnostic yield of culture 0-2%

Not recommended in immunocompetent pts
Abdominal
exploration
Role of surgery in post-CT era uncertain
Empiric Therapy
(antibiotics, anti-TB, steroids)
Not studied
Not recommended
Proposed Diagnostic Algorithm
Mourad, O. et al. Arch Intern Med 2003;163:545-551.
Back to the case
CBC and differential, electrolytes, BUN, creatinine, Ca/Mg/Ph all

normal
Liver enzymes very slightly elevated then normalized (AST
68normal, ALT 78normal), bilirubin, ALP normal
Multiple blood cultures: no growth
ESR 39
Hepatitis, Lyme, PPD, Mononucleosis, Q-fever, HIV serology all
negative, ANA, RF negative
CT thorax and abdomen normal
2D Echo normal
Leg dopplers negative
Skin biopsy: unremarkable epidermis and dermis, no subcutaneous
material obtained; lesions resolved
Back to the case

Fever
of > 40C continued for more than 4 weeks

No diagnosis despite multiple out-pt visits and a short
in-hospital stay
Debated about going to bone marrow biopsy versus
liver biopsy
Decided on nuclear scan
However, pt was given short course of oral antibiotics
by family MD, symptoms resolved, pt cancelled all
further tests and follow-up appointments with us and
is doing fine
Conclusions from Case

Given
our modern-day advances, prognosis in

patients who truly have no diagnosis after
extensive recommended work-up is very good
(most sinister diagnoses are discovered)
In some cases, spontaneous resolution occurs, in
others, watchful waiting is necessary (but often
frustrating)
1930s: > 30% of FUO with no diagnosis died
Today: 50-90% or more recover spontaneously

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Fever of Unknown Origin

AIMGP Seminar Series

O., et al. A Comprehensive EvidencedBased Approach to Fever of Unknown Origin.

Case Discussion Based on Real Patient

old female, born in Canada, parents from

Take a minute to discuss

she fit the criteria for Fever of

Fever of Unknown Origin - Definition

Temperature higher than 38.3C

recognizes acceptability of out-patient in place

on short duration and absence of

examination do you focus on during this initial

Four Proposed Categories of FUO

on potential etiology of FUO

Classic Category of FUO

outpatient visits or 3 days in-hospital

Infection, malignancy, CVD

This category will be the focus of this talk

Nosocomial Category of FUO

on admission, evaluation of at least 3 days

C.Difficile, drugs, PE, septic thrombophlebitis,

sinusitis (intubated patients)

candidiasis, herpes virus

HIV-Associated Category of FUO

3 days for inpatients, HIV confirmed

Etiology and Epidemiology

Infections: Most common cause accounting for 1/3 of cases

Malignancy: Second most common cause

CVD: Third most common cause

Diagnostic Approach - History

of fever, nature of fever curve, apparent

examination may be needed

Back to the case

history and physical noncontributory except for intermittent skin

what you know thus far, what

Suggested minimal diagnostic work-up to qualify as FUO has

History and physical examination

abnormal physical exam or liver enzymes exist

Diagnostic yield of culture 0-2%

Role of surgery in post-CT era uncertain

(antibiotics, anti-TB, steroids)

Proposed Diagnostic Algorithm

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

Back to the case

CBC and differential, electrolytes, BUN, creatinine, Ca/Mg/Ph all

Back to the case

of > 40C continued for more than 4 weeks

Conclusions from Case

our modern-day advances, prognosis in

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