Chapter 019. Fever of Unknown Origin (Part 6) pdf

Chapter 019. Fever of Unknown Origin
(Part 6)

Nosocomial FUO
(See also Chap. 125) The primary considerations in diagnosing nosocomial
FUO are the underlying susceptibility of the patient coupled with the potential
complications of hospitalization. The original surgical or procedural field is the
place to begin a directed physical and laboratory examination for abscesses,
hematomas, or infected foreign bodies. More than 50% of patients with
nosocomial FUO are infected. Intravascular lines, septic phlebitis, and prostheses
are all suspect. In this setting, the best approach is to 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 may
be associated with fever and leukocytosis before the onset of diarrhea. In ~25% of
patients with nosocomial FUO, the fever has a noninfectious cause. Among these
causes are acalculous cholecystitis, deep-vein thrombophlebitis, and pulmonary
embolism. Drug fever, transfusion reactions, alcohol/drug withdrawal, adrenal
insufficiency, thyroiditis, pancreatitis, gout, and pseudogout are among the many
possible causes to consider. As in classic FUO, repeated meticulous physical
examinations, coupled with focused diagnostic techniques, are imperative.
Multiple blood, wound, and fluid cultures are mandatory. The pace of diagnostic
tests is accelerated, and the threshold for procedures—CT scans, ultrasonography,
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In WBC scans, noninvasive venous studies—is low. Even so, 20% of cases of
nosocomial FUO may go undiagnosed.
Like diagnostic measures, therapeutic maneuvers must be swift and
decisive, as many patients are already critically ill. IV lines must be changed (and
cultured), drugs stopped for 72 h, and empirical therapy started if bacteremia is a
threat. In many hospital settings, empirical antibiotic coverage for nosocomial
FUO now includes vancomycin for coverage of methicillin-resistant
Staphylococcus aureus as well as broad-spectrum gram-negative coverage with

piperacillin/tazobactam, ticarcillin/clavulanate, imipenem, or meropenem. Practice
guidelines covering many of these issues have been published jointly by the
Infectious Diseases Society of America (IDSA) and the Society for Critical Care
Medicine and can be accessed on the IDSA website
(www.journals.uchicago.edu/IDSA/guidelines).
Neutropenic FUO
(See also Chap. 82) Neutropenic patients are susceptible to focal bacterial
and fungal infections, to bacteremic infections, to infections involving catheters
(including septic thrombophlebitis), and to perianal infections. Candida and
Aspergillus infections are common. Infections due to herpes simplex virus or
CMV are sometimes causes of FUO in this group. While the duration of illness
may be short in these patients, the consequences of untreated infection may be
catastrophic; 50–60% of febrile neutropenic patients are infected, and 20% are
bacteremic. The IDSA has published extensive practice guidelines covering these
critically ill neutropenic patients; these guidelines appear on the website cited in
the previous section. In these patients, severe mucositis, quinolone prophylaxis,
colonization with methicillin-resistant S. aureus, obvious catheter-related
infection, or hypotension dictates the use of vancomycin plus ceftazidime,
cefepime, or a carbapenem with or without an aminoglycoside to provide
empirical coverage for bacterial sepsis.
HIV-Associated FUO
HIV infection alone may be a cause of fever. Infection due to
Mycobacterium avium or Mycobacterium intracellulare, tuberculosis,
toxoplasmosis, CMV infection, Pneumocystis infection, salmonellosis,
cryptococcosis, histoplasmosis, non-Hodgkin's lymphoma, and (of particular
importance) drug fever are all possible causes of FUO. Mycobacterial infection
can be diagnosed by blood cultures and by liver, bone marrow, and lymph node
biopsies. Chest CT should be performed to identify enlarged mediastinal nodes.
Serologic studies may reveal cryptococcal antigen, and
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Ga scan may help
identify Pneumocystis pulmonary infection. FUO has an infectious etiology in
>80% of HIV-infected patients, but drug fever and lymphoma remain important
considerations. Treatment of HIV-associated FUO depends on many factors and is
discussed in Chap. 182.
Fever of Unknown Origin: Treatment
The focus here is on classic FUO. Other modifiers of FUO—neutropenia,
HIV infection, a nosocomial setting—all vastly affect the risk equation and dictate
therapy based on the probability of various causes of fever and on the calculated
risks and benefits of a guided empirical approach. The age and physical state of
the patient are factors as well: the frail elderly patient may merit a trial of
empirical therapy earlier than the robust young adult.
The emphasis in patients with classic FUO is on continued observation and
examination, with the avoidance of "shotgun" empirical therapy. Antibiotic
therapy (even that for tuberculosis) may irrevocably alter the ability to culture
fastidious bacteria or mycobacteria and delineate ultimate cause. However, vital-
sign instability or neutropenia is an indication for empirical therapy with a
fluoroquinolone plus piperacillin or the regimen mentioned above (see
"Nosocomial FUO"), for example. Cirrhosis, asplenia, intercurrent
immunosuppressive drug use, or recent exotic travel may all tip the balance
toward earlier empirical anti-infective therapy. If the PPD skin test is positive or if
granulomatous hepatitis or other granulomatous disease is present with anergy
(and sarcoid seems unlikely), then a therapeutic trial with isoniazid and rifampin
(and possibly a third drug) should be undertaken, with treatment usually continued
for up to 6 weeks. A failure of the fever to respond over this period suggests an
alternative diagnosis.
The response of rheumatic fever and Still's disease to aspirin and
nonsteroidal anti-inflammatory drugs (NSAIDs) may be dramatic. The effects of
glucocorticoids on temporal arteritis, polymyalgia rheumatica, and granulomatous
hepatitis are equally dramatic. Colchicine is highly effective in preventing attacks

of familial Mediterranean fever but is of little use once an attack is well under
way. The ability of glucocorticoids and NSAIDs to mask fever while permitting
the spread of infection dictates that their use be avoided unless infection has been
largely ruled out and unless inflammatory disease is both probable and debilitating
or threatening.
When no underlying source of FUO is identified after prolonged
observation (>6 months), the prognosis is generally good, however vexing the
fever may be to the patient. Under such circumstances, debilitating symptoms are
treated with NSAIDs, and glucocorticoids are the last resort. The initiation of
empirical therapy does not mark the end of the diagnostic workup; rather, it
commits the physician to continued thoughtful reexamination and evaluation.
Patience, compassion, equanimity, and intellectual flexibility are indispensable
attributes for the clinician in dealing successfully with FUO.