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
Investigations and the Evidence
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
Investigations and the Evidence
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
Investigations and the Evidence
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
Investigations and the Evidence
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