Download Fever

FUO Basics
Patty W. Wright, MD & C. Buddy Creech, MD, MPH
with appreciation to
William Goins, MD and Bryan Youree, MD
March 2011
Objectives

To discuss
 the definition of fever of unknown origin
(FUO)
 the classifications of FUO
 the most common etiologies of FUO
 the diagnostic work-up of patients with
FUO
What is a normal body
temperature?
Normal Body Temperature (Adults)

1 million axillary temperatures measured
twice daily in 25,000 healthy adults

Mean temperature: 37°C (36.2 – 37.5°C)

Readings >38.0°C were deemed as
“suspicious/probably febrile”

Thermometers may have read 1.4 – 2.2°C
(2.6 – 4.0°F) higher than today’s instruments
Wunderlich C. Das Verhalten der Eigenwärme in Krankenheiten. Leipzig, Germany: Otto Wigard;1868.
Mackowiak, et al., JAMA 1992;268:1578
Normal Body Temperature (Adults)
Patients
148 healthy adults
Method
Oral temp with electronic thermometer
Frequency
1 – 4 times daily for 3 days
Mean
36.8 ± 0.4°C (98.2 ± 0.7°F)
Upper limits
of normal
37.2°C (98.9°F) in the early morning
37.7°C (99.9°F) overall
Mackowiak, et al., JAMA 1992;268:1578
Normal Body Temperature (Adults)

Mean temperature varied diurnally



Low: 6 AM
Peak: 4 – 6 PM
Mean variability: 0.5°C (0.9°F)

Women had slightly higher
temperatures

Black subjects tended to have higher
temperatures than whites
Mackowiak, et al., JAMA 1992;268:1578
Normal Temperature Curves
(Children)
What is hyperthermia?
Hyperthermia



Unregulated
elevation of
temperature
Does not involve
hypothalamic
thermoregulatory
center
Cytokines not
directly involved
Mechanisms of Hyperthermia
1.
•
•
•
•
•
•
2. Disorders of heat
Excessive heat
dissipation
production
• Heat stroke
Exertional
• Autonomic
hyperthermia
dysfunction
Thyrotoxicosis
Pheochromocytoma
3. Disorders of
Cocaine
hypothalamic function
Delerium tremens
• Neuroleptic
Malignant
malignant syndrome
hyperthermia
• CVA
• Trauma
What is fever?
Fever



Resetting of the thermostatic set-point
in the anterior hypothalamus
Initiation of heat-conserving
mechanisms
Cytokine-mediated
What is a
Fever of Unknown Origin?
Fever of Unknown Origin

Temp > 101°F (38.3°C) on several
occasions

Fever of at least 3 weeks duration

No diagnosis after a 1 week evaluation
in the hospital or (in the modern era) a
reasonable outpatient work-up
Petersdorf RG, Beeson PB. Medicine 1961;40:1-30.
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
HIVassociated
Patient’s
situation
Hospitalized,
acute care, no
infection when
admitted
Neutrophil
Confirmed
count <500/µL HIV-positive
or expected to
reach that level
in 1-2 days
Duration of
illness
3 days b
3 days b
Classic
All others
with fevers
for ≥3
weeks
3 days b
3 days b or
3 outpatient
(or 4 weeks
as outpatient) visits
require temperatures of ≥38.3°C (101°F) on several occasions.
bIncludes at least 2 days’ incubation of microbiology cultures.
aAll
Modified from DT Durack, AC Street, in JS Remington, MN Swartz (eds):
Current Clinical Topics in Infectious Diseases. Cambridge, MA, Blackwell, 1991.
What are the three most common
causes of FUO (in general)?
Classifications of FUO
Modified from DT Durack in Mandell, Bennett, and Dolin. Principles and Practice of Infectious Diseases, 2005. 6th ed.
Evolving Etiology of FUO in Adults
Mourad, et al. Arch Intern Med. 2003;163:545
Magnitude of Fever

102°F rule



Most noninfectious disorders in adults are
associated with temperatures ≤ 102°F
Best used to exclude noninfectious causes
of fever
106°F

Temperatures ≥ 106°F are rarely due to
infection

Examples: central fever, drug fever, NMS,
malignant hyperthermia
Causes of FUO in Adults
Type
Infections
Common
TB
 Extrapulmonary
 Renal
 Meningitis
 Miliary
 Intra-abdominal
abscess
 Liver
 Splenic
 Pancreatic
 Perinephric
 Psoas
 Placental
Pelvic abscess
Uncommon
SBE
CMV
Toxo
Salmonella enteric
fever
Intra/perinephric
abscess
Splenic abscess
Rare
Dental abscess
Brain abscess
Vertebral osteo
Listeria
Yersinia
Brucellosis
Relapsing Fever
Rat-bite fever
Chronic Q fever
Cat-scratch fever
HIV
EBV
Malaria
Whipple’s disease
Cunha BA. Fever of unknown origin. Infect Dis Clin North Am 1996;10:111-127.
What is the most common
malignancy causing FUO?
Causes of FUO
Type
Common
Malignancy Lymphoma
Liver/CNS mets
Hypernephromas
Uncommon
Hepatomas
Pancreatic CA
Preleukemias
Colon CA
Rare
Atrial myxomas
CNS tumors
Myelodysplastic
diseases
Cunha BA. Fever of unknown origin. Infect Dis Clin North Am 1996;10:111-127.
Causes of FUO
Type
Common
Rheumatologic
Still’s disease
Temporal
Arteritis
Uncommon
PAN
RA
Rare
SLE
Vasculitis
Felty’s syndrome
ARF
Behcet’s disease
FMF
Cryoglobulinemia
Reiter’s syndrome
Rheumatic fever
Wegener’s
disease
Sarcoidosis
Cunha BA. Fever of unknown origin. Infect Dis Clin North Am 1996;10:111-127.
Causes of FUO
Type
Misc
Common
Drug Fever
Cirrhosis
Alcoholic hepatitis
Uncommon
Granulomatous
hepatitis
Cerebrovascular
accident
Rare
Hyperthyroidism
Addison’s disease
PE/DVT
Kikuchi’s disease
Hyper IgD
syndrome
Crohn’s disease
Ulcerative colitis
Cunha BA. Fever of unknown origin. Infect Dis Clin North Am 1996;10:111-127.
Drug Fever






Diagnosis of exclusion
Approximately 10% of fevers in hospitalized
patients
Look “well”
Relative bradycardia may occur
Usually no rash
Fever usually returns to normal within 3 days

May take longer if accompanied by a rash
*****************************************
Johnson DH, Cunha BA. Drug fever. Infect Dis Clin North Am 1996;10:85-91.
Causes of FUO in Children
Series
Cases
Infxn
CVD
Neoplasm
Misc
Undiagnosed
McClung (60’s)
99
29%
11%
8%
19%
32%
Pizzo (70’s)
100
52%
20%
6%
10%
12%
Steele (80’s)
109
22%
6%
2%
3%
67%
Chantada
(80’s)
113
36%
13%
10%
22%
19%
Muoaket (80's)
221
78%
5%
2%
-
15%
Most common infectious etiologies in children:
Bartonella, EBV, CMV, Histoplasmosis,
Blastomycosis, TB
What is periodic fever?
Periodic Fever


Periodic is different
from sporadic,
intermittent,
occasional
Periodicity involves
having repeated
cycles appearing at
regular intervals
Periodic Fever Syndromes

Non-familial


PFAPA (Periodic Fever, Aphthous Stomatitis,
Pharyngitis, and Adenitis)
Familial






Familial Mediterranean Fever (FMF)
Hyper IgD Syndrome (HIDS)
TNF-receptor associated periodic syndrome
(TRAPS or Hibernian Fever)
Muckle-Wells Syndrome (MWS)
Familial Cold Urticaria (FCU)
Cyclic Hematopoesis (CH)
PFAPA Case Definition






Periodic fevers beginning before the age of 5
years
At least one clinical criterion (ulcers, pharyngitis,
adenitis)
Absence of cough, purulent rhinitis, or otitis on
examination
Asymptomatic periods between attacks
Normal growth and development
Exclusion of cyclic neutropenia
PFAPA Registry (Vanderbilt)


In 1997, parents of registry patients were
contacted by telephone to collect information
on patients believed by their physicians to
have PFAPA
94 patients were available, 83 with long-term
follow-up data
Characteristics of PFAPA Patients
Original Registry
Follow-up
Number of Patients
94
83
Female
42
36
Male
52
47
Onset of PFAPA
2.8 years
-
Duration of each episode
4.8 days
4.2 days
Episodes per year
11.5
10.0
Symptom-free Interval
28.2 days
41.2 days **
Thomas KT, et al. J Pediatr. 1999;135:15-21.
PFAPA Symptoms, by Report
Original Registry (66)
Follow-up (82)
Aphthous Ulcers
67%
70%
Pharyngitis
65%
72%
Lymphadenopathy
77%
88%
Chills
80%
80%
Cough
20%
13%
Coryza
18%
15%
Headache
65%
60%
Abdominal pain
45%
49%
Rash
15%
9%
Thomas KT, et al. J Pediatr. 1999;135:15-21.
Efficacy of Treatment
Treatment
No. of
Episode
s
Not
Effective
Somewhat
Effective
Moderately
Effective
Very
Effective
Acetaminophen
80
55%
26%
15%
6%
Ibuprofen
67
15%
31%
21%
33%
Antibiotics
71
92%
6%
0%
3%
Prednisone
49
10%
4%
10%
76%
Cimetidine
28
57%
4%
11%
29%
Tonsillectomy
4
25%
0%
25%
50%
T&A
47
14%
14%
0%
72%
Thomas KT, et al. J Pediatr. 1999;135:15-21.
Familial Periodic Fever Syndromes
FMF
TRAPS
HIDS
MWS/FCU
CH
Duration of
Attack
1-3 days
Days-weeks
3-7 days
Days-weeks
4-7 days
Clinical
Features
Serositis;
Conjunctivitis, Cervical
scrotal pain myalgias
adenitis,
vomiting
Urticaria,
deafness,
cold
intolerance
Aphthous
stomatitis,
adenitis
Skin
Erysipelaslike lesions
Tender red
plaques
Maculopapular rash
Urticaria
Furuncles
Amyloidosis
Frequent
Variable
Low risk
Very
Frequent
Unknown
Inheritance
AR
AD
AR
AD
AD
Ancestry
Jewish,
Turkish,
Armenian
Scottish/Irish
Dutch, French
German,
English,
French
None
What is the diagnostic work up
for FUO?
Diagnostic Testing for FUO in
Children

First tier


Second tier


CBC, CMP, blood/urine cultures, ESR/CRP, EBV,
CMV, CSD serology, TST
Fungal serology; CT chest, abdomen, pelvis with
contrast
Third tier

Gallium or Indium scan; bone scan
*****************************************
Diagnostic Algorithm for FUO in Adults
Complete History and Physical Assessment
Positive Findings
Yes
Order appropriate and
specific diagnostic testing
No
CBC w/ diff, chemistries, LFTs, blood cultures x3, UA, urine culture, ESR, CRP,
ANA, RF, HIV ab, PPD, CXR
Positive Results
No
Yes
Order appropriate follow-up
diagnostic testing
CT of chest/abdomen/pelvis with
contrast
Adapted from Roth AR, Basello GM. Approach to the Adult Patient with fever of unknown origin. Am Fam Physician.
2003;68:2223-8.
Additional Workup for FUO in Adults



If symptoms of “mono” syndrome
 CMV antibodies
 EBV antibodies
 HIV viral load
 Toxoplasmosis serologies
If exposure risk factors
 Q-fever serology
If abnormal liver enzyme test results
 Viral hepatitis serologies
Mourad, et al. Arch Intern Med. 2003;163:545
Diagnostic Algorithm for FUO in Adults
Assign to most likely category
Infection
Urine & sputum
cultures for
AFB, VDRL,
HIV test, CMV &
EBV serology
Malignancies
Hematologic
Nonhematologic
Autoimmune
Miscellaneous
RF, ANA
Order
appropriate
diagnostic tests
based on
information from
history
Mammography, Chest
Peripheral
CT with contrast,
smear, SPEP Upper/lower endoscopy,
bone scan, gallium scan
No Dx?
No Dx?
No Dx?
No Dx?
TTE/TEE, LP,
gallium scan,
sinus films
BM biopsy
Brain MRI; Biopsy
of LN, skin lesions,
or liver
TA biopsy, LN
biopsy
Roth AR, Basello GM. Approach to the Adult Patient with fever of unknown origin. Am Fam Physician. 2003;68:2223-8.
Liver Biopsy & Bone Marrow Biopsy



Diagnostic yield of
liver biopsy 14% 17%
Hepatomegaly on
exam or abnormal
LFT’s not helpful in
predicting abnormal
biopsy result
Complication rate
0.06% - 0.32%
Mourand et al. Arch Intern Med 2003;163:545

Diagnostic yield of
bone marrow
cultures in
immunocompetent
individuals 0% - 2%
Volk et al. J Clin Pathol 1998;110:150
Riley et al. J Clin Pathol 1995:48:706
FUO Prognosis



Determined primarily by the underlying
disease
Outcome worst for neoplasms
If undiagnosed after extensive
evaluation, adults generally have
favorable outcome and fever usually
resolves after 4-5 weeks
Larson et al. Medicine 1982;61:269
Where is the world’s tallest
thermometer?
WORLD'S TALLEST THERMOMETER
BAKER, CALIFORNIA
*****************************************
Case Presentation- “Connor”




Connor is an 18 month old male with a one
year history of periodic fevers to 104.
Between each ‘episode’ the child has grown
well and has appeared healthy and active
Occasionally there are uncomplicated URI’s
and gastroenteritis, but these episodes seem
‘different.’
What additional information would you like to
obtain from Connor’s parents?
Case Presentation- “Connor”

During each episode, his parents report that
he has pharyngitis and aphthous ulcers in the
mouth.

What disease do you think Connor has and
how would treat him?
PFAPA

Treatment is with prednisone 2mg/kg as a
single dose at the beginning of each episode.




Rarely, children will require a second dose 24 hrs
later.
Treatment typically results in immediate resolution
of fever and other symptoms.
Primary side effect of treatment is shortening
of the interval between episodes.
PFAPA typically spontaneously resolves prior
to adolescence.
Case Presentation- “Kyle”




Kyle is a 7 year old male with daily fever to
103 for 3 weeks and a 10-pound weight
loss. He denies other symptoms.
He reports no unusual exposures or travel.
He attends 2nd grade.
On examination, his temperature is 104.
There are no focal findings, though there
is a hint of abdominal discomfort.
How would you proceed with his work-up?
Case Presentation- “Kyle”





CBC WNL. EBV and CMV titers c/w past
infection.
ALT 60. AST 36.
ESR 52. CRP 9 (nml < 10).
Abdominal ultrasound normal.
What additional work up would you consider
at this time?
Cat Scratch Disease



Abdominal CT confirmed
small microabscesses in
the spleen and liver
Bartonella serologies
revealed an IgG>1:512
consistent with diagnosis
of disseminated CSD
Additional history
revealed that the patient’s
family bought a new kitten
about 1 month prior to
presentation.
Cat Scratch Disease




Treatment not recommended for otherwise
uncomplicated CSD in kids
Treatment with azithromycin is recommended
for patients who are immunocompromised
May consider treatment for disseminated
disease
While a h/o scratches and local skin
eruption/LAD are common, they are not
universal.
*****************************************
Case Presentation- “Bill”


Bill is a 74 year old male with CAD and
HTN who present to the clinic c/o fever.
He reports fevers to 101.7 over the past
week. He reports associated fever and
malaise. He denies associated GI, GU,
or URI symptoms. This is his first health
care visit for his fevers.
Does Bill have an FUO?
Case Presentation - “Bill”


Bill has fever (T>101), but the duration
is < 3 wks, and he has not had an
evaluation.
Bill has a fever of unknown etiology, but
not an FUO.
Case Presentation - “Bill”


Bill’s physical exam is negative. Bill has a
CBC with diff which shows a mild anemia.
U/A was negative. Chemistries and LFT’s
were WNL. Bill is advised that he likely has a
viral infection and is prescribed
acetaminophen, po fluids, and rest. Bill
returns to the clinic 1 week later with
continued fevers.
What additional history should be obtained?
Case Presentation- “Bill”

Additional history…
 Travel history, recent & any h/o international
travel
 Animal exposures
 Sick contacts
 Family history of fevers
 Medications, including herbals & OTC meds

Bill denies any travel, animal or sick contact
exposure, or FH of fevers. His meds are stable
and include ASA, a beta-blocker, & a statin.
Case Presentation- “Bill”


Bill’s physical exam remains negative. He
has additional lab studies including blood and
urine cultures, ANA, RF, and HIV ab, all of
which are negative. Chest x-ray shows no
acute disease. PPD is negative. ESR is
elevated at 126 (normal < 20). CRP is 153
(normal < 10).
What disease do you think Bill has, and how
would you diagnose it?
Case Presentation- “Bill”

Temporal arteritis






May present with only fever and fatigue
May have associated HA, jaw claudication, or
visual changes
May note nodules or diminished temporal artery
pulsations on exam
ESR typically > 50 mm/hr and often > 100 mm/hr
Dx with temporal artery biopsy
 May need removal of extensive segments as
can have patchy involvement of the artery
Rx with steroids
Temporal Arteritis
(Giant Cell Arteritis)
www.neuropathologyweb.org
Case Presentation- “Sara”


Sara is a 30 year old female graduate student
who presents to your office with fevers to 101.5
for the past month. She reports associated flank
pain and dysuria without N/V/D. Exam was
negative.
She has been previously evaluated in the
student health clinic on 3 occasions. On her first
visit, she was noted to have a U/A positive for
leukocyte esterase with a negative urine culture.
She was given trim-sulfa x 3 days without
improvement.
Case Presentation- “Sara”


On her second visit, she had a repeat U/A with
micro which showed 10-20 WBC with a negative
urine cx. She was treated with levofloxacin x 14
days. Her fevers improved while on abx;
however, they returned after her abx were
d/c’ed.
On her third visit, a CBC w/ diff showed a mild
leukocytosis. Her chemistries and LFT’s were
WNL. KUB was negative. U/A again had + WBC,
so she was treated empirically with
metronidazole without relief.
Case Presentation- “Sara”

Does Sara have an FUO?

What additional history would you
like to obtain?
Case Presentation- “Sara”

Sara has had fevers > 101 for > 3 wks and
has undergone a basic work-up. She meets
the definition of FUO.

Additional history…





Travel history, recent & any h/o international travel
Animal exposures
Sick contacts
Family history of fevers
Sexual history
Case Presentation- “Sara”






Sara reports that she grew up in South Africa
and came to the US at 18 years of age to attend
college.
She has a pet iguana.
She denies sick contacts w/ similar symptoms.
No family history of fevers.
She is sexually active with her boyfriend of 6
months. He is her second life-time sexual
partner.
What additional studies would you obtain at this
time?
Case Presentation- “Sara”

Additional studies…





Gyn exam with STD screening, including tests
for GC, chlamydia, HIV, and trichomonas
CT of abdomen and pelvis
Blood cultures
You also recommend a PPD, but Sara states
that she had BCG vaccination as a child.
Do you proceed with PPD testing?
Case Presentation- “Sara”

Yes. In the US, we ignore prior BCG
vaccination status when interpreting PPD
results (i.e. a positive is still a positive
regardless of prior vaccination).
www.stanford.edu
Case Presentation- “Sara”



Sara’s gyn exam and STD screen are
negative. Her CT shows scarring of the
right kidney.
She returns at 48 hrs to have her PPD
read. She has 12 mm of induration.
Does Sara have a positive or negative
PPD?
Case Presentation- “Sara”
Patient Status
Positive
Result
HIV +
>5mm
Healthy individuals with
exposure history or risk
factors
>10mm
Healthy individuals with no
exposure history
>15mm
www.stanford.edu
Case Presentation- “Sara”

What disease do you think Sara has,
and how would you diagnose it?
www.cdc.gov
Case Presentation- “Sara”

Renal Tuberculosis
Culture of 3 morning urine specimens for
mycobacteria establishes the diagnosis
in 80% to 90% of cases
 Urine TB PCR has a sensitivity of 87100% and specificity of 92-99.8%

Renal TB
www.vetmed.wsu.edu
Summary





FUO is often a diagnostic dilemma
Infections, inflammatory disorders, and
malignancy account for the majority of cases
Diagnostic approach should occur in a stepwise fashion based on the H&P
Up to 30% of FUO’s in the modern era are
undiagnosed
Patients that remain undiagnosed generally
have a good prognosis
What are your questions?