Med II
Fever of Unknown Origin (FUO)
Denise
 FUO: defined by Petersdorf & Beeson in 1961 as:
(1)temp >38.3°C (>101°F) on several occasions
(2) duration of >3wks
(3) failure to reach a diagnosis despite 1wk of inpatient
investigation
 New system for classification of FUO:
(1) classic FUO
(2) nosocomial FUO
(3) neutropenic FUO
(4) FUO assoc with HIV infection
Classic FUO
 Corresponds closely to the earlier definition of
FUO, differing only with regard to the prior
requirement for 1wk’s study in the hospital
 New def’n: 3 outpatient visits or 3days in the
hospital without explanation of a cause or 1wk of
"intelligent and invasive" ambulatory investigation
Nosocomial FUO
 Temp = 38.3°C (=101°F) develops on several
occasions in a hospitalized px who is receiving
acute care & in whom infection was not manifest or
incubating on admission
 Min. requirement for diagnosis: 3 days of
investigation, including at least 2 days’ incubation
of cultures
Neutropenic FUO
 Temp = 38.3°C (=101°F) on several occasions in a px
whose neutrophil count is <500/uL or is expected to
fall to that level in 1-2days
 Diagnosis invoked if a specific cause is not
identified after 3days of investigation including at
least 2 days’ incubation of cultures
HIV-associated FUO
 Temp = 38.3°C (=101°F) on several occasions over a
period of >4wks for outpatients or >3days for
hospitalized pxs with HIV infection
 Diagnosis invoked if appropriate investigation over
3 days, including 2 days' incubation of cultures,
then reveals no source
Causes of Classic FUO
 Infections (especially extrapulmonary TB): leading
diagnosable cause of FUO
 Prolonged mononucleosis syndromes caused EBV, CMV
or HIV: can be a cause of FUO but sometimes
confounded by delayed Ab responses
 Intraabdominal, renal, retroperitoneal & paraspinal
abscesses: continue to be difficult to diagnose
 Renal malacoplakia with submucosal plaques or
nodules involving the UT:
 may cause FUO & often fatal if left untreated
 associated with coliform infection seen most
often in pxs with defects of intracellular
bacterial killing
 treated with fluoroquinolones or trimethoprim-
sulfamethoxazole
 Prostatitis, dental abscesses, sinusitis, and
cholangitis: continue to be sources of occult fever
 Other considerations:
 Osteomyelitis
 Infective endocarditis
 Slow-growing organisms
- Haemophilus aphrophilus
- Actinobacillus actinomycetemcomitans
- Cardiobacterium hominis,
- Eikenella corrodens
- Kingella kingae
- Bartonella spp. (previously Rochalimaea)
- Legionella spp.
- Coxiella burnetii
- Chlamydia psittaci
- fungi
 Neoplasms: 2nd most common cause of FUO after
infections
 But recently, there is a ↓ in the % of FUO cases
due to malignancy because of improvement in
diagnostic techniques (high-resolution CT &
tumor Ag assays)
 Noninfectious inflammatory diseases: systemic
rheumatologic or vasculitic diseases such as
polymyalgia rheumatica, lupus, adult Still’s disease as
well as granulomatous diseases such as sarcoidosis &
Crohn’s & granulomatous hepatitis
 Multisystem disease: most frequent cause of FUO in
the elderly
 Giant cell arteritis: leading etiologic entity in this
category
 TB: most common infection causing FUO in the
elderly
 Colon cancer: impt cause of FUO with malignancy in
the elderly
 Miscellaneous diseases causing FUO:
 Drug fever
- common drugs causing this: antimicrobial
agents (especially β-lactams), CV drugs
(e.g., quinidine), antineoplastic drugs & CNS
drugs (e.g., phenytoin)
 Pulmonary embolism
 Factitious fever
 Hereditary periodic fever syndromes (familial
Mediterranean fever, hyper-IgD syndrome, tumor
necrosis factor receptor-associated periodic
syndrome)
 Familial cold urticaria,
 Muckle-Wells syndrome
 Fabry's disease
 As duration of fever ↑, likelihood of an infectious
cause ↓ even for the more indolent infectious
etiologies (brucellosis, paracoccidioidomycosis, P.
malariae)
Specialized Diagnostic Studies
I. Classic FUO (See flow chart Fig. 18-1)
 Potentially diagnostic clues (DeKleijn &
colleagues)
 Key findings in the hx (e.g., travel)
 Localizing signs
 Key symptoms
 If factitious fever is suspected:
 electronic thermometers should be used
 temp-taking supervised
 simultaneous urine & body temp should be
measured
 Thick blood smears: for Plasmodium & to identify
Babesia, Trypanosoma, Leishmania, Rickettsia &
Borrelia
 Relevant radiologic reports reexamined
 Serum: should be set aside in the lab ASAP &
retained for future use for rising Ab titers
 Febrile agglutinins: serologic studies for
salmonellosis, brucellosis & rickettsial diseases;
but this test is seldom useful, having low
sensitivity & variable specificity
 Multiple blood samples (at least 3): cultured for
at least 2wks to ensure that any HACEK group
organisms may have ample time to grow
 Lysis-centrifugation blood culture techniques: in
cases where prior antimicrobial therapy or fungal
or atypical mycobacterial infection is suspected
 Blood culture media: supplemented with L-
cysteine or pyridoxal to assist in the isolation of
nutritionally variant streptococci
 Urine culture: for mycobacteria, fungi & CMV
  CSF testing + PCR: for herpesvirus in the setting
of recurrent fevers with lymphocytic meningitis
with use of PCR to amplify & detect viral nucleic
acid
 Striking elevation of the ESR & anemia of chronic
disease:
 Seen in assoc with giant cell arteritis or
polymyalgia rheumatica which are common
causes of FUO in pxs >50y/o
 Also suggests Still’s disease accompanied by
arthralgias, polyserositis, lymphadenopathy,
splenomegaly & rash
 C-reactive protein: for cross-reference for the
ESR; more sensitive & specific indicator of an
“acute-phase” inflammatory metabolic response
 To rule out other collagen vascular diseases &
vasculitic:
 Antinuclear-Ab
 Antineutrophil cytoplasmic Ab
 Rheumatoid factor
 Serum cryoglobulins
 Elevated levels of ACE in serum may be
sarcoidosis
 Intermediate-strength purified protein derivative
(PPD skin test): to screen for TB in pxs with
classic FUO
 Concurrent control tests that should be
employed: mumps skin test antigen (Aventis-
Pasteur, Swiftwater, PA)
 Noninvasive procedures:
 Upper GI contrast study with small bowel
follow-thru
 Colonoscopy: to examine the terminal ileum
& cecum
 CXR
 Sputum: induced with an ultrasonic nebulizer
for cultures & cytology
 Bronchoscopy with bronchoalveolar lavage
for cultures & cytology if with pulmonary S/S
 High-resolution spiral CT of chest & abdomen
performed with both IV & oral contrast
 MRI: preferred if with spinal or paraspinal
lesion; superior to CT in demonstrating
intraabdominal abscesses & aortic dissection
 Arteriography: useful for pxs in whom
systemic necrotizing vasculitic is suspected
 US of abdomen: for investigation of the
hepatobiliary tract, kidneys, spleen & pelvis
 Echocardiography: evaluation of bacterial
endocarditis & atrial myxomas, specifically
transesophageal echocardiography
 Radionuclide scanning using Tc99m sulfur colloid,
Ga67 citrate or In111-labeled leukocytes: to
identify or localize inflammatory processes
 Tc99m bone scan: for osteomyelitis or bony
metastases
 Ga67 scan: for sarcoidosis & Pneumocystis in
the lungs or Crohn’s disease
 In111-labeled WBC scan: to locate abscesses
 PET scanning: provides quicker results which will
prove even more sensitive & specific in FUO
 Biopsy of the liver & bone marrow: considered in
the FUO work-up
 Cultured for bacteria, mycobacteria & fungi
 PCR technology: to identify & speciate
mycobacterial DNA in paraffin-embedded, fixed
tissues
 Exploratory laparotomy: when all other
diagnostic procedures fail
 Laparascopic biopsy: provide more adequate
guided sampling of lymph nodes or liver
II. Nosocomial FUO
 Primary considerations: underlying susceptibility
of the px + potential complications of
hospitalization
 >50% with Nosocomial FUO are infected, &
intravascular lines, septic phlebitis & prostheses
are all suspect
 Focus on sites where occult infections may be
sequestered, such as the sinuses of intubated
patients or a prostatic abscess in a man with a
urinary catheter
 Clostridium difficile colitis: assoc with fever &
leukocytosis before the onset of diarrhea
 ~25% of pxs with nosocomial FUO, the fever has a
noninfectious cause. Among these causes are:
 Acalculous cholecystitis
 Deep-vein thrombophlebitis
 Pulmonary embolism
 Drug fever
 Transfusion reactions
 Alcohol/drug withdrawal
 Adrenal insufficiency
 Thyroiditis
 Pancreatitis
 Gout & pseudogout
 Mandatory procedures: multiple blood, wound &
fluid cultures
 IV lines must be changed (and cultured), drugs
stopped for 72h & empirical therapy started if
bacteremia is a threat
 Empirical antibiotic coverage for nosocomial
FUO: vancomycin for coverage of MRSA &
piperacillin/tazobactam, ticarcillin/clavulanate,
imipenem or meropenem for gram (-) coverage
III. Neutropenic FUO
 Pxs with this are susceptible to:
 focal bacterial infections
 fungal infections
 bacteremic infections
 infections involving catheters
 perianal infections
 Candida & Aspergillus: also common
 Infections due to HSV & CMV: also causes FUO
 Duration of illness may be short in these pxs, the
consequences of untreated infection may be
catastrophic; 50 to 60% of febrile neutropenic
patients are infected, and 20% are bacteremic
 Indications for the use of vancomycin plus
ceftazidime, cefepime, or a carbapenem with or
without an aminoglycoside to provide empirical
coverage for bacterial sepsis
 severe mucositis
 quinolone prophylaxis
 colonization with MRSA
 obvious catheter-related infection
 hypotension
IV. HIV-Associated FUO
 HIV infection alone may be a cause of fever
 Possible causes:
 Mycobacterium avium or Mycobacterium
intracellulare
 TB
 Toxoplasmosis
 CMV infection
 Pneumocystis infection
 Salmonellosis
 Cryptococcosis
 Histoplasmosis
 Non-Hodgkin's lymphoma
 Drug fever
 Can be diagnosed by blood cultures & by liver,
bone marrow & lymph node biopsies
 Chest CT: performed to identify enlarged
mediastinal nodes
 Serologic studies: reveal cryptococcal antigen
 Ga76 scan: help identify Pneumocystis pulmonary
infection
Treatment
 Focus here is on classic FUO
 Factors that may affect tx:
 Neutropenia
  HIV infection
 Nosocomial setting
 Age
 Physical state of px
- frail elderly patient may merit a trial of
empirical therapy earlier than the robust
young adult
 Continued observation and examination, with the
avoidance of "shotgun" empirical therapy
 Antibiotic therapy (even that for TB) may irrevocably
alter the ability to culture fastidious bacteria or
mycobacteria and delineate ultimate cause
 Vital-sign instability or neutropenia: indication for
empirical therapy with a fluoroquinolone +
piperacillin
 Indications of earlier empirical anti-infective therapy
 Cirrhosis
 Asplenia
 Intercurrent immunosuppressive drug use
 Recent exotic travel
 If PPD skin test is (+): a therapeutic trial with
isoniazid & rifampin with tx continued for up to 6wks
 A failure of the fever to respond over this period
suggests an alternative diagnosis
 Aspirin & NSAIDS may have dramatic effects on the ff
diseases that may cause FUO:
 Rheumatic fever
 Still's disease
 Effects of glucocorticoids on temporal arteritis,
polymyalgia rheumatica, and granulomatous hepatitis
are equally dramatic
 Colchicine: highly effective in preventing attacks of
familial Mediterranean fever but is of little use once
an attack is well under way
 Avoid use of glucocorticoids and NSAIDs since they
mask fever while permitting the spread of infection
unless inflammatory disease is both probable and
debilitating or threatening.
 Good prognosis: when no underlying source of FUO is
identified after prolonged observation (>6 months)
 Debilitating symptoms may be treated with
NSAIDS & glucocorticoids will be the last resort