CHAPTER 10

FEVER OF UNKNOWN ORIGIN

Jeffrey A. Gelfand Michael V. Callahan

DEFINITION AND CLASSIFICATION

Fever of unknown origin (FUO) was defined by Petersdorf and Beeson in 1961 as (1) temperatures
of >38.3°C (>101°F) on several occasions; (2) a duration of fever of >3 weeks; and (3) failure to
reach a diagnosis despite 1 week of inpatient investigation. While this classification has stood for
more than 30 years, Durack and Street have proposed a revised system for classification of FUO that
better accounts for nonendemic and emerging diseases, improved diagnostic technologies, and
adverse reactions to new therapeutic interventions. This updated classification includes (1) classic
FUO, (2) nosocomial FUO, (3) neutropenic FUO, and (4) FUO associated with HIV infection.
Classic FUO corresponds closely to the earlier definition of FUO, differing only with regard to
the prior requirement for 1 week’s study in the hospital. The newer definition is broader, stipulating
three outpatient visits or 3 days in the hospital without elucidation of a cause or 1 week of “intelligent
and invasive” ambulatory investigation. In nosocomial FUO, a temperature of ≥38.3°C (≥101°F)
develops on several occasions in a hospitalized patient who is receiving acute care and in whom
infection was not manifest or incubating on admission. Three days of investigation, including at least
2 days’ incubation of cultures, is the minimum requirement for this diagnosis. Neutropenic FUO is
defined as a temperature of ≥38.3°C (≥101°F) on several occasions in a patient whose neutrophil
count is <500/μL or is expected to fall to that level in 1–2 days. The diagnosis of neutropenic FUO is
invoked if a specific cause is not identified after 3 days of investigation, including at least 2 days’
incubation of cultures. HIV-associated FUO is defined by a temperature of ≥38.3°C (≥101°F) on
several occasions over a period of >4 weeks for outpatients or >3 days for hospitalized patients with
HIV infection. This diagnosis is invoked if appropriate investigation over 3 days, including 2 days’
incubation of cultures, reveals no source.
Adoption of these categories of FUO in the literature has allowed a more rational compilation of
data regarding these disparate groups. In the remainder of this chapter, the discussion will focus on
classic FUO in the adult patient unless otherwise specified.

CAUSES OF CLASSIC FUO

Table 10-1 summarizes the findings of several large studies of FUO carried out since the advent of
the antibiotic era, including a prospective study of 167 adult patients with FUO encompassing all
eight university hospitals in the Netherlands and using a standardized protocol in which the first
author reviewed every patient’s case. Coincident with the widespread use of antibiotics, increasingly
useful diagnostic technologies—both noninvasive and invasive—have been developed. Newer
studies reflect not only changing patterns of disease but also the impact of diagnostic techniques that
make it possible to eliminate many patients with specific illness from the FUO category. The
ubiquitous use of potent broad-spectrum antibiotics may have decreased the number of infections
causing FUO. The wide availability of ultrasonography, CT, MRI, radionuclide scanning, and
positron emission tomography (PET) scanning has enhanced the detection of localized infections and
of occult neoplasms and lymphomas in patients previously thought to have FUO. Likewise, the
widespread availability of highly specific and sensitive immunologic testing has reduced the number
of undetected cases of adult Still’s disease, systemic lupus erythematosus, and polyarteritis nodosa.

TABLE 10-1
CLASSIC FUO IN ADULTS
 Infections such as extrapulmonary tuberculosis and—in endemic areas—typhoid fever and malaria
remain a leading diagnosable cause of FUO. Prolonged mononucleosis syndromes caused by Epstein-
Barr virus, cytomegalovirus (CMV), or HIV are conditions whose consideration as a cause of FUO
are sometimes confounded by delayed antibody responses. Intraabdominal abscesses (sometimes
poorly localized) and renal, retroperitoneal, and paraspinal abscesses continue to be difficult to
diagnose. Renal malacoplakia, with submucosal plaques or nodules involving the urinary tract, may
cause fatal FUO if untreated; it is associated with intracellular bacterial infection, is seen in patients
with defects of intracellular bacterial killing, and is treated with fluoroquinolones or trimethoprim-
sulfamethoxazole. Occasionally, other organs may be involved. Osteomyelitis, especially where
prosthetic devices have been implanted, must be considered. Although true culture-negative infective
endocarditis is rare, one may be misled by cryptic endocarditis caused by indolent, slow-growing
microorganisms of the HACEK group (Haemophilus aphrophilus, Aggregatibacter [formerly
Actinobacillus] actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and
Kingella kingae), Bartonella spp. (previously Rochalimaea), Legionella spp., Coxiella burnetii,
Chlamydophila psittaci, and fungi. Prostatitis, dental abscesses, sinusitis, and cholangitis continue to
be sources of occult fever.
Fungal diseases, most notably histoplasmosis involving the reticuloendothelial system, may cause
FUO, particularly outside of the endemic regions where these diseases may be more readily
recognized. FUO following travel to neotropical regions and the desert southwest of the United
States, even for very limited periods, should prompt evaluation for paracoccidioidomycosis and
coccidioidomycosis, respectively. The rising popularity of adventure travel among citizens of
Western countries has increased the incidence in these nations of presentation for FUO due to
otherwise uncommon endemic vector-borne infections, notably chikungunya fever and scrub typhus.
FUO with headache should prompt examination of spinal fluid for Cryptococcus neoformans,
Mycobacterium tuberculosis, and travel-acquired trypanosomes. Malaria (which may result from
transfusion, failure to take a prescribed prophylactic agent, or infection with a drug-resistant
Plasmodium strain) continues to be a cause of FUO, particularly of the asynchronous variety. A
related protozoan infection, babesiosis, may cause FUO and is increasing in geographic distribution
and in incidence, especially among the elderly and the immunosuppressed.
In most earlier series, neoplasms were the next most common cause of FUO after infections (Table
10-1). In more recent series, a decrease in the percentage of FUO cases due to malignancy was
attributed to improvement in diagnostic technologies—in particular, high-resolution tomography,
MRI, PET scanning, and tumor antigen assays. This observation does not diminish the importance of
considering neoplasia in the initial diagnostic evaluation of a patient with fever. A number of patients
in these series had temporal arteritis, adult Still’s disease, drug-related fever, and factitious fever. In
recent series, ~25–50% of cases of FUO have remained undiagnosed. The general term noninfectious
inflammatory diseases applies to systemic rheumatologic or vasculitic diseases such as polymyalgia
rheumatica, lupus, and adult Still’s disease as well as to granulomatous diseases such as sarcoidosis,
Crohn’s disease, and granulomatous hepatitis.
In the elderly, multisystem disease is the most frequent cause of FUO, giant-cell arteritis being the
leading etiologic entity in this category. In patients >50 years of age, this disease accounts for 15–
20% of FUO cases. Tuberculosis is the most common infection causing FUO in the elderly, and colon
cancer is an important cause of FUO with malignancy in this age group.
Many diseases have been grouped in the various studies as “miscellaneous.” On this list are drug
fever, pulmonary embolism, factitious fever, the hereditary periodic fever syndromes [familial
Mediterranean fever, hyper-IgD syndrome, tumor necrosis factor (TNF) receptor–associated periodic
syndrome (also known as TRAPS or familial Hibernian fever), familial cold urticaria, and the
Muckle-Wells syndrome)], and congenital lysosomal storage diseases such as Gaucher’s and Fabry’s
disease.
A drug-related etiology must be considered in any case of prolonged fever. Any febrile pattern
may be elicited by a drug. Virtually all classes of drugs can cause fever, but antimicrobial agents
(especially β-lactam antibiotics), cardiovascular drugs (e.g., quinidine), antineoplastic drugs, and
drugs acting on the central nervous system (e.g., phenytoin) are particularly common causes. The use
of TNF inhibitors for treatment of inflammatory diseases has led to atypical presentations of
tuberculosis, histoplasmosis, coccidioidomycosis, and JC virus infection associated with FUO.
It is axiomatic that, as the duration of fever increases, the likelihood of an infectious cause
decreases, even for the more indolent infectious etiologies (e.g., brucellosis,
paracoccidioidomycosis, malaria due to Plasmodium malariae). In a series of 347 patients referred
to the National Institutes of Health from 1961 to 1977, only 6% had an infection (Table 10-2). A
significant proportion (9%) had factitious fevers—i.e., fevers due either to false elevations of
temperature or to self-induced disease. A substantial number of these factitious cases were in young
women in the health professions. It is worth noting that 8% of the patients with prolonged fevers
(some of whom had completely normal liver function studies) had granulomatous hepatitis, and 6%
had adult Still’s disease. After prolonged investigation, 19% of cases still had no specific diagnosis.
A total of 27% of patients had no actual fever during inpatient observation or had an exaggerated
circadian temperature rhythm without chills, elevated pulse, or other abnormalities.

TABLE 10-2
CAUSES OF FUO LASTING >6 MONTHS
GLOBAL CONSIDERATIONS

More than 200 conditions may be considered in the differential diagnosis of classic FUO in
adults; the most common of these are listed in Table 10-3. This list applies predominantly to Western
nations such as the United States. The workup of FUO must take into careful consideration the
patient’s country of origin, recent and remote travel (including past service in foreign wars), unusual
environmental exposures associated with travel or hobbies (e.g., caving, hunting, and safaris), and
pets. The increasing number of returning sojourners with exotic travel itineraries underscores the
need for a detailed history of travel and associated activities in the setting of undiagnosed fever, as
do the changing demographics of the travelers themselves. For example, increasing numbers of
travelers are immunosuppressed, are undergoing disease-modifying interventions such as TNF-α
suppression, or have recently reconstituted immunity. Immigrants with unexplained fever, including
naturalized citizens who have left their countries of origin decades previously, should be carefully
interviewed with regard to childhood exposures, including immunization with nonstandard or
unidentified live vaccines. In both foreign-born individuals and veterans of foreign wars, subclinical
infections may be unmasked decades after exposure by new malignancies or immunosuppressive
conditions. The differential diagnosis of FUO must also take into account changes in the range of
arthropod vectors or the possibility that local permissive vectors have become infected with
previously nonendemic pathogens. Evaluation of FUO in under-resourced medical settings requires
increased reliance on history and clinical examination. Patients, family members, and close
occupational contacts may need to be interviewed. If specialized laboratory and imaging studies
cannot be conducted, diagnosis may be facilitated by maximizing the quality and precision of locally
available approaches (e.g., culture of lysed, centrifuged blood cultures and microscopic examination
by an experienced technician). Emerging infectious diseases may include FUO first presenting as
clusters of cases in remote regions; insight may be gained from contacting local epidemiologists.

TABLE 10-3
CAUSES OF FUO IN ADULTS IN THE UNITED STATES
 The possibility of international and domestic terrorist activity involving the intentional release of
infectious agents, many of which cause illnesses presenting with prolonged fever, underscores the
need for obtaining an insightful environmental, occupational, and professional history, with early
notification of public health authorities in cases of suspicious etiology (Chap. 7). Moreover, the
global spread of genetic engineering technologies raises the possibility that traditional agents—
including Centers for Disease Control Categories A, B, and C agents; see Table 7-2)—that
circumvent vaccine-acquired immunity could be developed or that novel recombinant organisms
could be engineered to produce clinical or laboratory responses that defy current diagnostic
approaches.

SPECIALIZED DIAGNOSTIC STUDIES

Classic FUO
A stepwise flow chart depicting the diagnostic workup and therapeutic management of FUO is
provided in Fig. 10-1. In this flow chart, reference is made to “potentially diagnostic clues,” as
outlined by de Kleijn and colleagues; these clues may be key findings in the history (e.g., travel),
localizing signs, or key symptoms. Certain specific diagnostic maneuvers become critical in dealing
with prolonged fevers. If factitious fever is suspected, temperature-taking should be supervised, and
simultaneous urine and body temperatures should be measured. Thick blood smears should be
examined for Plasmodium; thin blood smears, prepared with proper technique and quality stains and
subjected to expert microscopy, should be used to speciate Plasmodium and to identify Babesia,
Trypanosoma, Leishmania, Leptospira, Rickettsia, and Borrelia. Specialized staining of
mononuclear cells and granulocytes can help to identify intracellular bacteria, protozoal amastigotes,
and the inclusion bodies of ehrlichiosis and anaplasmosis. Any tissue removed during prior relevant
surgery should be reexamined; slides should be requested, and, if necessary, paraffin blocks of fixed
pathologic material should be reexamined and additional special studies performed. Relevant x-rays
should be reexamined; review of prior radiologic reports may be insufficient. Serum should be set
aside in the laboratory as soon as possible and retained for future examination for rising antibody
titers.
FIGURE 10-1
Approach to the patient with classic FUO. a“Potentially diagnostic clues,” as outlined by de Kleijn
and colleagues (1997, Part II), may be key findings in the history, localizing signs, or key symptoms.
b Needle biopsy of liver as well as any other tissue indicated by “potentially diagnostic clues.”
cInvasive testing could involve laparoscopy. d Empirical therapy is a last resort, given the good
prognosis of most patients with FUO persisting without a diagnosis. Abbreviations: ANA, antinuclear
antibody; CBC, complete blood count; CMV, cytomegalovirus; CRP, C-reactive protein; CT,
computed tomography; Diff, differential; EBV, Epstein-Barr virus; ESR, erythrocyte sedimentation
rate; FDG, fluorodeoxyglucose F18; NSAIDs, nonsteroidal anti-inflammatory drugs; PET, positron
emission tomography; PMN, polymorphonuclear leukocyte; PPD, purified protein derivative; RF,
rheumatoid factor; SPEP, serum protein electrophoresis; TB, tuberculosis; TIBC, total iron-binding
capacity; VDRL, Venereal Disease Research Laboratory test.

Febrile agglutinins is a vague term that, in most laboratories, refers to serologic studies for
salmonellosis, brucellosis, and rickettsial diseases. These studies are seldom useful, having low
sensitivity and variable specificity. Multiple blood samples (no fewer than three and rarely more than
six, including samples for anaerobic culture) should be cultured in the laboratory—with and without
increased CO2—for 2 to 3 weeks to ensure ample growth time for any HACEK organisms (Chap. 51).
It is critical to inform the laboratory of the intent to test for unusual organisms. Specialized media
should be used if an exposure or travel history suggests uncommon causes of endocarditis, such as
Histoplasma, Chlamydophila, Mycoplasma, Bartonella, Coxiella, or Tropheryma whipplei. Blood
culture media should be supplemented with L-cysteine or pyridoxal to assist in the isolation of
nutritionally variant streptococci. Lysis-centrifugation blood culture techniques should be employed
when prior antimicrobial therapy or fungal or atypical mycobacterial infection is suspected. It should
be noted that sequential cultures positive for multiple organisms may reflect self-injection of
contaminated substances. Cultures of sinus fluid and pulmonary secretions on multiple permissive
cell lines may prove helpful in identifying new respiratory viruses implicated in FUO. Urine cultures,
including cultures for mycobacteria, fungi, and CMV, are indicated. In the setting of recurrent fevers
with lymphocytic meningitis (Mollaret’s meningitis), cerebrospinal fluid can be tested for
herpesvirus, with use of the polymerase chain reaction (PCR) to amplify and detect viral nucleic acid
(Chap. 84). A highly multiplexed oligonucleotide microarray using PCR amplification and containing
probes for all recognized virus species hosted by vertebrates and up to 135 bacterial, 73 fungal, and
63 parasitic genera and species has been developed but has not yet been approved for clinical use.
The continued clinical validation of such microarrays will further diminish rates of undiagnosed FUO
of infectious etiology.
In any FUO workup, the erythrocyte sedimentation rate (ESR) should be determined. Striking
elevation of the ESR and anemia of chronic disease are frequently seen in association with giant cell
arteritis or polymyalgia rheumatica—common causes of FUO in patients >50 years of age. Still’s
disease is suggested by elevations of ESR, leukocytosis, and anemia and is often accompanied by
arthralgias, polyserositis (pleuritis, pericarditis), lymphadenopathy, splenomegaly, and rash. The C-
reactive protein level may be a useful cross-reference for the ESR and is a more sensitive and
specific indicator of an “acute-phase” inflammatory metabolic response. Antinuclear antibody,
antineutrophil cytoplasmic antibody, rheumatoid factor, and serum cryoglobulins should be measured
to rule out other collagen vascular diseases and vasculitis. Elevated levels of angiotensin-converting
enzyme in serum may point to sarcoidosis. With rare exceptions, the intermediate-strength purified
protein derivative (PPD) skin test should be used to screen patients with classic FUO for
tuberculosis. Concurrent control tests, such as the mumps skin test antigen (Aventis-Pasteur,
Swiftwater, PA), should be employed. It should be kept in mind that both the PPD tuberculin skin test
(TST) and control tests may yield false-negative results in patients with miliary tuberculosis,
sarcoidosis, Hodgkin’s disease, malnutrition, or AIDS. Two interferon γ–release assays have been
approved by the U.S. Food and Drug Administration for the diagnosis of tuberculosis. These tests—
the QuantiFERON-TB Gold In-Tube (QFT-GIT) assay and the T-SPOT TB assay—measure the
production of interferon γ by T lymphocytes upon exposure to antigens of M. tuberculosis. In direct
comparisons, the sensitivity of the QFT-GIT test was statistically similar to that of the TST for
detecting infection in persons with untreated, culture-confirmed tuberculosis. The QFT-GIT test is
more specific, is less influenced by previous infection with nontuberculous mycobacteria, and is not
affected by prior vaccination with bacille Calmette-Guérin (BCG); TSTs are variably affected by
these factors. Repeating the QFT-GIT test does not boost the in vitro response, while injection of
PPD for the TST can boost subsequent TST responses, primarily in persons who have been infected
with nontuberculous mycobacteria or vaccinated with BCG. Negative results in the QFT-GIT test—as
in the TST—do not definitively exclude a diagnosis of tuberculosis.
Noninvasive procedures should include an upper gastrointestinal contrast study with small-bowel
follow-through and colonoscopy to examine the terminal ileum and cecum for early evidence of
lymphoma or subclinical Crohn’s disease. Colonoscopy is especially strongly indicated in the
elderly. Chest x-rays should be repeated if new symptoms arise. Sputum should be induced with an
ultrasonic nebulizer for cultures, cytology, and molecular diagnostic testing. If there are pulmonary
signs or symptoms, bronchoscopy with bronchoalveolar lavage for cultures, PCR, and cytology
should be considered. High-resolution spiral CT of the chest and abdomen should be performed with
both IV and oral contrast. If a spinal or paraspinal lesion is suspected, however, MRI is preferred.
MRI may be superior to CT in demonstrating intraabdominal abscesses and aortic dissection, but the
comparative utility of MRI and CT in the diagnosis of FUO is unknown. At present, abdominal CT
with contrast should be used unless MRI is specifically indicated. Arteriography may be useful for
patients in whom systemic necrotizing vasculitis is suspected. Saccular aneurysms may be seen, most
commonly in renal or hepatic vessels, and may permit diagnosis of arteritis when biopsy is difficult.
Ultrasonography of the abdomen is useful for investigation of the hepatobiliary tract, kidneys, spleen,
and pelvis. Echocardiography may be helpful in an evaluation for bacterial endocarditis, pericarditis,
nonbacterial thrombotic endocarditis, and atrial myxomas. Transesophageal echocardiography is
preferred for these lesions.
Radionuclide scanning procedures using technetium (Tc) 99m sulfur colloid, gallium (Ga) 67
citrate, or indium (In) 111–labeled leukocytes may be useful in identifying and/or localizing
inflammatory processes such as aortitis or abscess. In one study, Ga scintigraphy yielded useful
diagnostic information in almost one-third of cases, and it was suggested that this procedure might
actually be used before other imaging techniques if no specific organ is suspected of being abnormal.
It is likely that PET scanning, which provides quicker results (hours vs days), will prove even more
sensitive and specific than 67Ga scanning in FUO. 99mTc bone scan should be undertaken to look for
osteomyelitis or bony metastases; 67Ga scan may be used to identify sarcoidosis or Pneumocystis
infection (Chap. 114) in the lungs or Crohn’s disease in the abdomen. 111In-labeled white blood cell
(WBC) scan may be used to locate abscesses. With these scans, false-positive and false-negative
findings are common. Fluorodeoxyglucose F18 (FDG) PET scanning appears to be superior to other
forms of nuclear imaging. The FDG used in PET scans accumulates in tumors and at sites of
inflammation and has even been shown to accumulate reliably at sites of vasculitis. Where available,
FDG PET scanning should therefore be chosen over 67Ga scanning in the diagnosis of FUO.
Biopsy of the liver and bone marrow should be considered in the workup of FUO if the studies
mentioned earlier are unrevealing and if fever is prolonged. Granulomatous hepatitis has been
diagnosed by liver biopsy, even when liver enzymes are normal and no other diagnostic clues point to
liver disease. All biopsy specimens should be cultured for bacteria, mycobacteria, and fungi.
Likewise, in the absence of clues pointing to the bone marrow, bone marrow biopsy (not simple
aspiration) for histology and culture has yielded diagnoses late in the workup. When possible, a
section of the tissue block should be retained for further sections or stains. At some research centers,
PCR technology makes it possible in some cases to identify and speciate mycobacterial DNA in
paraffin-embedded, fixed tissues. Thus, a retrospective diagnosis can sometimes be made on the basis
of studies of long-fixed pathologic tissues. In a patient over age 50 (or occasionally in a younger
patient) with the appropriate symptoms and laboratory findings, “blind biopsy” of one or both
temporal arteries may yield a diagnosis of arteritis. Tenderness or decreased pulsation, if noted,
should guide the selection of a site for biopsy. Lymph node biopsy may be helpful if nodes are
enlarged, but inguinal nodes are often palpable and are seldom diagnostically useful.
Exploratory laparotomy has been performed when all other diagnostic procedures fail but has
largely been replaced by imaging and guided-biopsy techniques. Peritoneal lavage may be used as a
minimally invasive approach to peritoneal cytology studies. Laparoscopic biopsy may provide more
adequate guided sampling of lymph nodes or liver, with less invasive morbidity.

Nosocomial FUO
(See also Chap. 14) 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, 111In 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 hours, and
empirical therapy started if bacteremia, fungemia, or persistently high virus loads are a threat. In
many hospital settings, empirical antibiotic therapy 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 American College of Critical Care Medicine and can be
accessed on the IDSA website (www.journals.uchicago.edu/IDSA/guidelines).

Neutropenic FUO
(See also Chap. 12) 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
(www.journals.uchicago.edu/IDSA/guidelines). 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. The infectious etiology varies with the extent of
immunosuppression and the geographic region. Infection due to Mycobacterium avium or M.
intracellulare, tuberculosis, toxoplasmosis, CMV infection, Pneumocystis infection, salmonellosis,
cryptococcosis, histoplasmosis, strongyloidiasis, 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 67Ga
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. 93.

TREATMENT Fever of Unknown Origin

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 earlier (see “Nosocomial FUO”, earlier
in the chapter).), for example. Cirrhosis, asplenia, disease-modifying biologic therapy, intercurrent
immunosuppressive drug use, or exotic travel or environmental exposures (e.g., cave interiors) may
all tip the balance toward earlier empirical anti-infective therapy. If the TST is positive or if
granulomatous hepatitis or other granulomatous disease is present with anergy (and sarcoid seems
unlikely), then a therapeutic trial for tuberculosis 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, vigilance, and intellectual flexibility are indispensable attributes for the clinician in
dealing successfully with FUO.

ACKNOWLEDGMENTS
Sheldon M. Wolff, MD, now deceased, was an author of a previous version of this chapter. It is to
his memory that the chapter is dedicated. The substantial contributions of Charles A. Dinarello,
MD, to this chapter in previous editions of Harrison’s Principles of Internal Medicine are
gratefully acknowledged.