THE LANCET

Seminar

Fever of unknown origin

Paul M Arnow, John P Flaherty
Diagnosis often involves pattern recognitionfor example,
thyrotoxicosis or rheumatoid arthritis commonly have a
constellation of distinctive clinical features and laboratory
tests are then done for confirmation. This approach is
more difficult when the clinical features are few, subtle, or
insufficient to characterise a disease or group of diseases.
Diagnosing the cause of fever is sometimes like this, and
the most perplexing of such cases are grouped under the
heading fever (or pyrexia) of unknown origin (FUO).
These cases are encountered once or twice a month at
teaching hospitals.14
FUO defies simplification. Reported causes exceed 200
(panel 1), and fall into diverse sub-specialty categories.
There are no algorithms and few clues that reliably
suggest or exclude particular diagnoses. The clinician
must rely on very careful evaluation and detailed
knowledge of a wide variety of diseases.

Definition
FUO means fever that does not resolve spontaneously in
the period expected for self-limited infection and whose
cause cannot be ascertained despite considerable
diagnostic effort. In 1961, Petersdorf and Beeson5
introduced the definition that subsequently became
standardnamely, illness of more than three weeks
duration, fever higher than 383C (101F) on several
occasions, and diagnosis uncertain after one week of
study in hospital. Because hospital admission is so
expensive and since thorough diagnostic testing now can
be done in outpatient settings, the definition recently was
modified to remove the requirement that hospital be the
setting for a week of evaluation.6,7 The definition does not
specifiy what constitutes this evaluation but the studies
listed in panel 2 are, we suggest, the minimum.
Recognition that the causes of unexplained fever in
patients with impaired immunity may differ from those in
classic FUO has prompted categories such as FUO in
cancer8,9 for FUO in HIV infection,10 groupings that help
formulate a more relevant and economical differential
diagnosis, as has also been done with FUO in elderly
patients11 and children.1214

Causes
The proportion of FUO cases grouped in specific disease
categories has changed little during the past four decades
(panel 3). Infection accounts for about one-third of cases,
followed by neoplasia and collagen vascular diseases. The
frequency of neoplasia declined in several recent series2,3,19
Lancet 1997; 350: 57580
Department of Medicine, Section of Infectious Diseases, University
of Chicago, University of Chicago Hospitals, Chicago, IL 60637,
USA (P M Arnow MD, J P Flaherty MD)
Correspondence to: Dr Paul M Arnow
(e-mail [email protected])

Vol 350 August 23, 1997

ostensibly due to improved diagnostic imaging,2 but in a

contemporaneous series the proportion was 24%.6 In our
hospital neoplasia, in particular lymphoma, remains an
important cause of FUO.
The role of certain individual diseases has changed
considerably. For example, rheumatic fever and systemic
lupus erythematosus (SLE) were common in early series
but are unusual today, probably because of the sharp
decline in rheumatic fever in the developed world and the
wide availability of accurate tests for SLE that permit
early diagnosis. Infective endocarditis has decreased in
frequency since the 1950s as blood culture techniques
have improved, but new pathogens that are difficult to
isolate (eg, Bartonella quintana) ensure that it will not
disappear as a cause of FUO. A few diagnoses in recent
series were unknown four decades ago, including Lyme
disease, acute HIV infection, Sweets syndrome, and
Bartonella endocarditis. Early series also failed to report
drug fever as a cause of FUO.

Diagnosis
The diagnostic approach in FUO has not been uniform
but has always included a thorough history, careful
physical examination, laboratory tests, and radiographic
studies. These modes of investigation interact so the
contribution of each to a diagnosis is difficult to assess,
even when the method of diagnosis or yield of a specific
test is reported.16,11,19 The difficulty is reflected by the
interval between hospital admission and diagnosis, which
averaged 19 days in two recent studies.2,6
The causes of FUO are usually familiar diseases with
uncommon presentations rather than rare disorders. In
several series of paediatric12,14 and adult6 cases the correct
diagnosis was possible from the history, physical
examination, and routine laboratory tests. Conversely,
failure to utilise findings correctly,13,14 delay in ordering
appropriate tests,2 and misinterpretation of test results12
have all contributed to missed diagnoses. Specialised noninvasive tests such as serology seldom help except to
confirm a diagnosis suggested by other findings.

History
A thorough history is important,16,20,21 and this should
include information about alcohol intake, medications,
occupational exposures, pets, travel, familial disorders,
and previous illnesses. Examples of diseases for which
clues were provided by the history include amoebiasis
(foreign travel), familial Mediterranean fever (family
history), psittacosis (contact with parakeets), metastatic
cancer (previous primary cancer), and drug fever
(medications). Awareness of prior inflammatory processes
in the abdomen is especially important; in a recent series,
8 of 9 patients with FUO due to intraabdominal
abscesses had Crohns disease or a prior episode of
cholecystitis, diverticulitis, or appendicitis.4 Specific
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complaints have not always been helpful. Only about

one-half of the patients with abdominal complaints
and about one-fourth of those with central-nervoussystem complaints had disease at the corresponding
site.14,15

Physical examination
The specific findings that have led to a diagnosis in FUO
are numerous and diverse. Examples included slight
enlargement of the thyroid (thyroiditis), periodontal
disease or loose teeth (dental abscess), thickened temporal
artery (temporal arteritis), cardiac murmur that changes
with position (atrial myxoma), and widespread
hyperpigmentation (Whipples disease). The key findings
can often be detected only by a very careful examination

and may be missed first time. Illustrating the

embarrassment that can arise from an incomplete
examination is a patient whose wound abscess at an
amputation stump was concealed by a prosthesis and was
missed by at least four different specialty services.1
The yield of the physical examination is not recorded in
most studies of FUO, other than to note that diagnostic
testing often was guided by abnormalities detected in the
initial evaluation. That the yield may be high is suggested
by two studies reporting that in paediatric patients about
60% had abnormal findings that contributed to a
diagnosis.13,14 In half of these cases, the abnormalities were
detected
only
by
repeat
examinations.14
Lymphadenopathy, which might be considered an
important finding, generally has not correlated with
specific illnesses or a positive biopsy.13,15

Panel 1: Causes of FUO*

Infection
Intraabdominal abscess (eg, periappendiceal, diverticular, subphrenic); liver, splenic, pancreatic, perinephric, psoas, or placental
abscess
Appendicitis, cholecystitis, cholangitis, aortoenteric fistula, mesenteric lymphadenitis, tubo-ovarian abscess, pyometra
Intracranial abscess, sinusitis, mastoiditis, otitis media, dental abscess
Chronic pharyngitis, tracheobronchitis, lung abscess
Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection
Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis
Tuberculosis, Mycobacterium avium complex, leprosy, Lyme disease, relapsing fever (Borrelia recurrentis), syphilis, Q fever,
legionellosis, yersiniosis
Salmonellosis (including typhoid fever), listeriosis, Campylobacter, brucellosis, tularaemia, bartonellosis, ehrlichiosis, psitticosis,
Chlamydia pneumoniae, murine typhus, scrub typhus
Gonococcaemia, meningococcaemia
Actinomycosis, nocardiosis, melioidosis, Whipples disease (Tropheryma whippelii)
Candidaemia, cryptococcosis, histoplasmosis, coccodioidomycosis, blastomycosis, sporotrichosis, aspergillosis, mucormycosis,
Malassezia furfur, Pneumocystis carinii
Visceral leishmaniasis, malaria, babesiosis, toxoplasmosis, schistosomiasis, fascioliasis, toxocariasis, amoebiasis, infected
hydatid cyst, trichinosis, trypanosomiasis
Cytomegalovirus, HIV, Herpes simplex, Epstein-Barr virus, parvovirus B19
Neoplasia
FUO has been reported in association with all common malignant diseases, and with 46 altogether
Collagen vascular disease
Adult Stills disease, SLE, cryoglobulinaemia, Reiters syndrome. rheumatic fever, giant cell arteritis/polymyalgia rheumatica,
Wegeners granulomatosis, ankylosing spondylitis, Behets syndrome, polyarteritis nodosa
Hypersensitivity vasculitis, urticarial vasculitis, Sjgrens syndrome, polymyositis, rheumatoid arthritis, erythema multiforme,
erythema nodosum, relapsing polychondritis, mixed connective-tissue disease, Takayasus aortitis, Weber-Christian disease,
Feltys syndrome, eosinophilic fasciitis
Miscellaneous
Haematoma, thrombosis, recurrent pulmonary embolism, aortic dissection, femoral aneurysm, post-myocardial infarction
syndrome, atrial myxoma
Drug fever, Sweets syndrome, familial Mediterranean fever, familial Hibernian fever, hyperimmunoglobulin D syndrome
Crohns disease, ulcerative colitis, sarcoidosis, granulomatous hepatitis
Subacute (de Quervains) thyroiditis, hyperthyroidism, adrenal insufficiency, primary hyperparathyroidism, hypothalamic
hypopituitarism, autoimmune haemolytic anaemia
Gout, pseudogout
Cirrhosis, chronic active hepatitis, alcoholic hepatitis, shunt nephritis
Malacoplakia, Kawasakis syndrome, Kikuchis syndrome
Mesenteric fibromatosis, inflammatory pseudotumour
Castlemans disease, Vogt-Koyanagi-Harada syndrome, Gaucher disease, Schnitzlers syndrome, FAPA syndrome (fever, aphthous
stomatitis, pharyngitis, adenitis), Fabrys disease
Cholesterol emboli, silicone embolisation, Teflon embolisation
Lymph node infarction, sickle cell disease vasoocclusive crisis, anhidrotic ectodermal dysplasia, cyclic neutropenia, Brewers
yeast ingestion, Hamman-Rich syndrome
Milk protein allergy, hypersensitivity pneumonitis, extrinsic allergic alveolitis, metal fume fever, polymer fume fever, idiopathic
hypereosinophilic syndrome
Complex partial status epilepticus, cerebrovascular accident, brain tumour, encephalitis
Anomalous thoracic duct, psychogenic fever, habitual hyperthermia, factitious illness
*Identified in case-reports and case series published during 196197.

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Clinical features
Although it is logical to try to narrow the differential
diagnosis in individual cases of FUO by focusing on
specific clinical features, this approach has helped little.
Fever has been characterised by magnitude and
frequency, and specific fever patterns have been ascribed
to many of the causes of FUO.22 Unfortunately, in most
case series, the height, pattern, or duration of fever did
not relate to diagnosis.3,1315 The few entities that usually
have a distinctive fever pattern (eg, non-falciparum
malaria or cyclic neutropenia) are rare, and fever patterns
thought to be distinctive for other diseases, such as PelEbstein fever in lymphoma, are seldom seen. Relative
bradycardia may be useful when present, although it is
associated with a substantial differential diagnosis,
including typhoid fever, legionnaires disease, psittacosis,
leptospirosis, drug fever, brucellosis, subacute necrotising
lymphadenitis, neoplasm and factitious fever. The
response of fever to naproxen sodium may be helpful in
that fever due to solid tumours and many
rheumatological diseases (most notably Stills disease)
usually subside promptly while fever due to other causes
may persist.23,24 Other features, such as sweats, chills, or
weight loss have not discriminated among causes of FUO.
The generalisation that FUO of very long duration is
unlikely to be due to infection is fairly reliable but applies
to few patients.
Laboratory tests
Non-invasive laboratory tests have provided a diagnosis in
perhaps one-quarter of FUO cases.6,18,19 These include
serological
tests
for
microbial
pathogens
or
rheumatological diseases. Paradoxically, the role of
enhanced culture systems in diagnosing cases of FUO is
probably diminishing because the commercial systems
that are now widely used are excellent at recovering
fastidious bacteria, mycobacteria, or fungi before the
conditions for FUO are met.
Imaging has been used primarily to localise
abnormalities for subsequent evaluation. Computed
tomography (CT) of the abdomen, in particular, has
increased the rate of positive results when subsequent
invasive diagnostic procedures are done.25 Structures that
appear abnormal by CT are almost always confirmed by
laparotomy or biopsy to be abnormal.26 The usefulness of
abdominal CT and occasionally ultrasound scanning of
the gallbladder and hepatobiliary system has resulted in
application of these tests to virtually all cases of FUO.

Panel 2: Minimum diagnostic evaluation to qualify as FUO

Comprehensive history
Repeated physical examination
Complete blood count, including differential and platelet count
Routine blood chemistry, including lactate dehydrogenase, bilirubin,
and liver enzymes
Urinalysis, including microscopic exmination
Chest radiograph
Erythrocyte sedimentation rate
Antinuclear antibodies
Rheumatoid factor
Angiotensin converting enzyme
Routine blood cultures (33) while not receiving antibiotics
Cytomegalovirus IgM antibodies or virus detection in blood
Heterophile antibody test in children and young adults
Tuberculin skin test
CT of abdomen or radionuclide scan
HIV antibodies or virus detection assay
Further evaluation of any abnormalities detected by above tests

Because of their extensive use, tabulated in one study at

more than three CT and/or ultrasound examinations per
patient,2 the yield per test has been only about 10%.2,11,27
False-negative CT results have occasionally been
reported, even with abscesses in solid organs, due to
distortions of normal anatomy, small abscess size, or
failure to use both oral and intravenous contrast agents.
In adults, the failure of ultrasound to detect many liver,
spleen, and intraperitoneal abscesses precludes reliance
on this examination.
Scanning with gallium-67 or indium-111 labelled
autologous leucocytes has been helpful when infection or
malignancy is the cause of FUO, and the overall yield
may be higher than that with CT or ultrasound.27,28
Positive results also have been reported with
diverse diseases including sarcoidosis, localised
Castlemans disease, thyroiditis, and giant-cell arteritis.
Limitations include false-negative gallium results with
secondary infected lesions (eg, haematomas or
pseudocysts) difficulty detecting splenic abscesses due to
a high level of background uptake in the spleen,
and a low positive predictive value with indium. A
promising new radiopharmaceutical, indium-111-labelled
immunoglobulin, appears very sensitive for the detection
of focal infection,29,30 and its eventual role in FUO
probably hinges on its accuracy in other fever-causing
conditions.

Panel 3: Distribution of FUO in adults by diagnostic category in eleven published series

Series

% of cases in specified diagnostic category*

Ref 5; 195257; n=100

Ref 15; 195960; n=60
Ref 16; 195771; n=128
Ref 17; 196976; n=100
Ref 1; 197080; n=105
Ref 18; 196881; n=133
Ref 2; 198089; n=199
Ref 6; 1984; n=86
Ref 3; 198292; n=153
Ref 4; 198892; n=53
Ref 19; 198692; n=80

Infection
36
22
40
37
30
31
23
33
29
21
54

Neoplasm
19
17
20
31
31
18
7
24
14
19
9

Collagen
vascular disease
15
13
15
19
9
13
19
16
29
13
14

Miscellaneous
23
10
17
8
17
17
28
18
16
17
5

Undiagnosed
7
38
8
5
12
21
24
9
12
30
18

*Diagnostic categories differ slightly from those used in some series

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Invasive procedures
Diagnosis in fewer than half the cases of FUO has
resulted from excisional biopsy, needle biopsy, or
laparotomy. Most FUO patients undergo at least one of
these procedures, even though the yield is moderateie,
2846 biopsies per final diagnosis achieved.1,6 The yield
from biopsies in the operating-theatre or under CT
guidance is greater than that of bedside biopsy
procedures.6 The only biopsy that may often be rewarding
in the absence of prior localising information is temporal
artery biopsy in elderly patients with a very high
erythrocyte sedimentation rate (ESR).11
Exploratory laparotomy in the absence of localising
features is unusual these days. Anatomical abnormalities
are unlikely to have been missed by CT, leaving only
diagnoses such as vasculitis, polyarteritis nodosa,
granulomatous disease, or chronic cholecystitis.26
Laparoscopy, including laparoscopic liver biopsy, is a less
traumatic alternative. It is most helpful when other
features point to abdominal disease and has had a yield of
only 20% when such features are absent.31 Liver biopsy
alone, in patients with or without recognised liver
abnormalities, is less helpful than laparoscopy.32
Approach
Attempting to diagnose the cause of FUO is a daunting
task. The list of possible causes is enormous; there are no
useful algorithms; and all tests that empirically have at
least a modest yield should already have been done.
Consequently, the clinician must rely on diligence
and clinical acumen. This admonition, however bland,
is relevant because newer diagnostic tests alone appear
to have had little impact on the incidence or causes of
FUO. Physicians should repeatedly interview and
examine the patient and review laboratory test results and
imaging studies, including those from other hospitals.
Delay often results from the failure to recognise helpful
clues in available information. Also, discontinue as many
medicines as possible and avoid procrastination when
faced with the need to obtain tissue for diagnosis.

Outcome
The prognosis is determined primarily by the underlying
disease and, to a lesser extent, by rapidity of diagnosis.
Outcome is worst for neoplasms.1 Diagnostic delay has
contributed to death in intraabdominal infection
(especially splenic abscess), miliary tuberculosis, disseminated fungal infection, and recurrent pulmonary emboli.
FUO patients who remain undiagnosed after extensive
evaluation generally have a favourable outcome1,3,5,33 and
the fever usually resolves after 45 weeks without
sequelae. A subgroup of patients with undiagnosed FUO
have clinical features which resemble polymyalgia
rheumatica, vasculitis, or other inflammatory disease but
do not meet accepted diagnostic criteria. These patients
may have fever which responds to corticosteroid therapy.

Selected diseases
In the following sketches of selected causes of FUO the
focus is on clinical features and laboratory tests likely to
be of diagnostic value.

Infections
Tuberculosis The forms of tuberculosis that most often
cause FUO are disseminated disease without the
578

characteristic miliary pattern on chest radiograph or

extrapulmonary disease without clear localising features.
Disseminated tuberculosis probably is the most readily
treatable cause of death in patients with FUO and
warrants vigorous diagnostic efforts when the disease is
suspected. Serial chest radiographs may demonstrate
subtle but increasing infiltrates. The ESR is usually raised
and anaemia is common. A tuberculin skin test may be
negative in up to one-half of patients and sputum smears
may be positive for acid-fast bacilli in only one-fourth to
one-half of cases. Lung and liver biopsy each demonstrate
granulomas in 8090% of cases of miliary tuberculosis;
about half the granulomas will show caseation and acidfast bacilli are seen in about half. Bone-marrow biopsy is
likely to show granulomas in only half the cases, but the
yield exceeds 80% when anaemia, leukopenia, and
monocytosis are present. Bronchoalveolar lavage is often
culture-positive but acid-fast bacilli are rare. Rapid
diagnostic tests (eg, PCR) permit earlier detection of
M tuberculosis and should be helpful in selected cases of
FUO. The most important measure is to obtain additional
specimens for histopathological and bacteriological
examination if the initial ones are negative but
tuberculosis is still suspected.

Intraabdominal abscess
The diverse sites of
intraabdominal abscess give rise to different clinical
features. Localising symptoms, such as abdominal pain,
nausea, vomiting, or diarrhoea, are common in liver or
intraperitoneal abscesses or chronic cholecystitis.
Tenderness on examination is reported in most cases of
liver, splenic, or intraperitoneal abscess. Elderly patients
typically have a more subacute course with few signs and
symptoms and a long illness. Certain antecedent
conditions predispose to specific intraabdominal
abscesseseg, Crohns disease to intraperitoneal or
retroperitoneal abscess and infective endocarditis, biliary
tract disease, and pancreatitis to abscess of the spleen,
liver, and pancreas, respectively.
Culture-negative endocarditis This has diminished in
importance as culture techniques have improved but
when it is suspected as the cause of FUO the laboratory
should be consulted about attempts to isolate unusual
pathogens by prolonged incubation (eg, two weeks rather
than five days), periodic staining of blood cultures with
acridine-orange, or blind subculture onto solid media.
Examples are by subculture onto blood agar and into
endothelial cell culture for Bartonella spp and onto
buffered charcoal-yeast extract agar for Legionella spp.
Coxiella burnetii is not recovered from routine blood
cultures, and serological testing is necessary. Even with
more typical endocarditis pathogens, antibiotics may
temporarily interfere with culture. Without a new
regurgitant murmur or evidence of peripheral emboli, the
diagnosis
may
be
obscure.
Transoesophageal
echocardiography is positive in over 90% of cases.
Cytomegalovirus One in four immunocompetent adults
with cytomegalovirus (CMV) mononucleosis has fever
lasting more than 3 weeks. The clinical presentation often
resembles mononucleosis but sore throat, pharyngeal
erythema, adenopathy, and splenomegaly are each present
in fewer than half the CMV cases. EBV and HIV can
cause a similarly protracted mononucleosis-like syndrome
but prolonged fever is suggestive of CMV. Every patient
with CMV should have reactive lymphocytosis and

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moderately increased serum transaminase at some point.

The diagnosis can be confirmed by serological testing
(CMV-IgM) or viral isolation from blood.

Neoplasms
Lymphoma
Fever is seen most often in advanced
lymphoma and with more aggressive histological patterns of
lymphoma. Constitutional, or B symptoms (fever, night
sweats and weight loss), are present in a minority of
lymphoma patients but on occasion dominate the clinical
presentation.
Lymphadenopathy,
splenomegaly,
unexplained anaemia or thrombocytopenia, and a very high
serum lactate dehydrogenase may provide clues. Careful
physical examination, a CT of chest, abdomen, and pelvis,
and bone marrow examination will usually identify the sites
of involvement. Biopsy may then confirm the diagnosis.
Renal-cell carcinoma
Renal cell carcinoma, or
hypernephroma, commonly causes fatigue and weight
loss, but intermittent fever may be the presenting
symptom in up to 15% of patients. The diagnosis may be
suggested by microscopic haematuria or erythrocytosis
linked to increased production of erythropoietin.
Abnormal liver-function tests are sometimes found in
patients without demonstrable liver metastases and often
resolve after removal of the primary tumour.
Atrial myxoma Manifestations include fever, syncope,
congestive heart failure, peripheral or pulmonary emboli,
weight loss, myalgias, arthralgias, and rash. Cardiac
murmur may be absent, intermittent, or positional; a lowpitched tumour plop is sometimes heard during diastole.
A raised ESR and anaemia are common. The diagnosis is
almost always established by echocardiograph y.
Collagen vascular diseases
Juvenile rheumatoid arthritis (Stills disease) The
diagnosis is based entirely on clinical features, including
fever, arthralgias, myalgias, arthritis, sore throat, diffuse
lymphadenopathy, splenomegaly, pleuritis, and pericarditis.
Fever may precede other features by a year. Fever usually is
high and may spike daily or twice-daily. An evanescent
macular rash sometimes becomes evident, primarily on the
trunk, during fever. Illness may be continuous or episodic,
with attacks separated by weeks or years. Anaemia,
leukocytosis, and a raised ESR are usual, and liver enzymes
are sometimes elevated. In active disease, serum ferritin
levels are very high. Biopsy of lymph nodes shows reactive
hyperplasia and biopsy of skin lesions shows perivascular
infiltration by chronic inflammatory cells. The triad of high
fever, evanescent rash, and arthritis or arthralgia in a young
adult strongly suggests Stills disease, especially if sore
throat is also reported.
Temporal arteritis Temporal arteritis (or giant-cell
arteritis) is very rare under age 55 but accounts for about
15% of FUO in the elderly. The disease classically
presents with headache, fever, anaemia, and a very high
ESR. Other symptoms include fatigue, anorexia, weight
loss, sweats, arthralgias, and depression, and patients may
complain of scalp pain, jaw claudication, or visual
disturbances. The temporal artery is tender, thickened, or
nodular on examination in a minority of patients.
Temporal artery biopsy is required to confirm the
diagnosis. Polymyalgia rheumatica is closely associated
with temporal arteritis and is characterised by pain and
stiffness in the muscles of the neck, shoulders, lower back,

Vol 350 August 23, 1997

hips, and thighs. A dramatic response to glucocorticoid

therapy can confirm the diagnosis. In an elderly patient
with unexplained fever, systemic symptoms, and a very
high ESR, temporal biopsy should be considered even if
there are no specific signs of arteritis.

Polyarteritis nodosa The clinical manifestations vary.

Malaise, myalgias, and fever are usually present and
specific features reflect involvement of the arteries in
organs such as the kidneys and gastrointestinal tract.
Features that are highly specific include mononeuritis,
testicular tenderness, and livedo reticularis. The patient will
often have antineutrophil cytoplasmic antibodies and
raised white-blood-cell count and ESR; hepatitis B surface
antigen has been detected in at least 15% of patients.
Diagnosis can be made by biopsy or by arteriography to
demonstrate aneurysms or narrowing of arteries.

Miscellaneous
Sarcoidosis This systemic disease most commonly affects
the lungs, skin, eyes, and lymph nodes. There is no
diagnostic blood test; angiotensin-converting enzyme
activity is raised in about two-thirds of patients but falsepositive and false-negative results are common. The chest
radiograph will almost always show bilateral hilar
adenopathy and/or diffuse parenchymal infiltrates. Biopsy
evidence of a mononuclear cell, granulomatous
inflammatory process establishes the diagnosis.
Haematoma Uninfected haematoma can elicit a feverproducing inflammatory response. Most haematomas
associated with FUO have been intraabdominal or
retroperitoneal and can be visualised by CT. A notable
exception is arterial wall haematoma associated with
aortic dissection, where the abrupt onset of chest, back, or
abdominal pain precedes the fever and anaemia.
Subacute thyroiditis The typical features of subacute
thyroiditis are thyroid pain and tenderness, accompanied
by malaise, myalgia, and fever. The onset is usually
sudden, and about half the cases are preceded by an
upper respiratory infection. Pain may be sensed in the
throat rather than the neck and may radiate to the ears or
jaw. Some degree of thyroid enlargement and tenderness
is almost always present. Relapses may prolong the course
of illness to many months. Diagnosis of subacute
thyroiditis is most difficult when thyroid pain and
tenderness are minimal.
Factitious fever
Factitious fever and self-induced
infection should be suspected when the clinical syndrome
does not correspond to a known disease. Clinical clues
include high temperatures without tachycardia or skin
warmth, unusual fever patterns (eg, very brief spikes or
loss of evening peak), and absence of fever when an
observer is present. Deception by thermometer
manipulation and thermometer switching is less common
where mercury bulb thermometers have been replaced by
rapid electronic thermometers. A remaining mechanism is
surreptitious ingestion of fever-causing drugs. True infections have been self-induced by injection of body fluids or
other contaminated materials. The resulting illnesses are
characterised by unexplained polymicrobial bacteraemia,
serial episodes of bacteraemia by different pathogens, or
recurrent soft-tissue infections (cellulitis or subcutaneous
abscesses). Patients with factitious fever or self-induced
infection are more likely to be female and often have a
medical, nursing, or paramedical background.
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Familial Mediterranean fever This illness is characterised

by periodic attacks of fever and abdominal pain,
sometimes accompanied by pleuritic chest pain, joint
pain, or painful skin lesions on the legs. In rare instances,
there may be episodes of fever alone or bouts of
abdominal pain without fever. Attacks usually begin
before adolescence. Each episode lasts only a few days but
may continue for more than a week, with intervals
between attacks of several weeks. Laboratory
abnormalities during attacks are leukocytosis and
raised ESR and acute-phase reactants. Familial
Mediterranean fever appears to be transmitted as an
autosomal recessive trait and occurs primarily, but not
exclusively, in ethnic groups of Middle-Eastern origin.
Diagnosis may be difficult in patients who lack the typical

family history or ethnic origin, or when peritoneal signs

are absent.

Drug fever The clinical characteristics of drug fever are

not distinctive. Fever patterns are diverse, shaking chills
occur in about half the cases, and rash or eosinophilia are
infrequent. Commonly, several weeks elapse between
initiation of the drug and onset of fever. Once the
causative drug is stopped, fever almost always resolves
within two days. The list of implicated agents is lengthy
and includes some drugs given to treat fever (eg, aspirin,
nonsteroidal antiinflammatory drugs, and antibiotics).
Diagnosis may be especially difficult when infection
prompted administration of the drugeg, isoniazid for
tuberculosis or vancomycin for suspected bacteraemia.

References
1

3
4

5
6
7
8

10

11
12
13
14
15
16
17
18

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Knockaert DC, Vanneste LJ, Vanneste SB, Bobbaers HJ. Fever of
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Iikuni Y, Okada J, Kondo H, Kashiwazaki S. Current fever of unknown
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Luft FC, Rissing JP, White A, Brooks GF. Infections or neoplasm as
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Knockaert DC, Vanneste LJ, Bobbaers HJ. Fever of unknown origin in
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Further reading

Causes
Knockaert DC, Vanneste LJ, Bobbaers HJ. Recurrent or episodic fever of
unknown origin: review of 45 cases and survey of the literature.
Medicine 1993: 72: 18496.
Ponce-de-Leon-Rosales S, Molina-Gamboa J, Rivera-Morales I. The
changing spectrum of fever of unknown origin in Mexico. Clin Infect
Dis 1994; 19: 353.

Diagnosis
de Kleijn EMHA, van der Meer JWM. Inquiry into the diagnostic workup
of patients with fever of unknown origin. Neth J Med 1997; 50: 6974.
Peters AM. Localising the cause of an undiagnosed fever. ur J Nucl Med
1996; 23: 23942.

Selected diseases
Cohen JI, Corey GR. Cytomegalovirus infection in the normal host.
Medicine 1985; 64: 10014.
Copper GS, Shlaes DM, Salata RA. Intraabdominal infection: differences
in presentation and outcome between younger patients and the elderly.
Clin Infect Dis 1994; 19: 14648.

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19

20
21
22
23

24

25
26

27

28

29

30

31
32

33

of unknown origin: changing spectrum of diseases in two consecutive

series. Postgrad Med J 1992; 68: 88487.
Shoji S, Imamura A, Imai Y, et al. Fever of unknown origin: a review of
80 patients from the Shinetsu area of Japan from 19861992. Intern
Med 1994; 33; 7476.
Esposito AL, Gleckman RA. A diagnostic approach to the adult with
fever of unknown origin. Arch Intern Med 1979; 139: 57579.
Brusch JL, Weinstein L. Fever of unknown origin. Med Clin N Am
1988; 72: 124760.
Cunha BA. The clinical significance of fever patterns. Infect Dis Clin N
Am 1996; 10: 3344.
Chang JC, Gross HM. The utility of naprosyn in the differential
diagnosis of fever of undetermined origin in patients with cancer. Am J
Med 1984; 76: 597603.
Wouters JM, Van de Putte LB. Adult-onset Stills disease: clinical and
laboratory features, treatment, and progress of 45 cases. Q J Med 1986;
61: 105565.
Rowland MD, Del Bene VE. Use of body computed tomography to
evaluate fever of unknown origin. J Infect Dis 1987; 156: 40809.
Quinn MJ, Sheedy PF II, Stephens DH, Hattery RR. Computed
tomography of the abdomen in evaluation of patients with fever of
unknown origin. Radiology 1980; 136: 40711.
Knockaert DC, Mortelmans LA, De Roo MC, Bobbaers HJ. Clinical
value of gallium-67 scintigraphy in evaluation of fever of unknown
origin. Clin Infect Dis 1994; 18: 60105.
Syrjala MT, Valtonen V, Liewendahl K, Myllyl G. Diagnostic
significance of indium-111 granulocyte scinitgraphy in febrile patients.
J Nucl Med 1987; 28: 15560.
Rubin RH, Fischman AJ, Callahan RJ, et al. 111In-labeled nonspecific
immunoglobulin scanning in the detection of focal infection. N Engl J
Med 1989; 321: 93540.
de Kleijn EMHA, Oyen WJG, Claessens RAMJ, Corstens FHM,
van der Meer JWM. Utility of scintigraphic methods in patients
with fever of unknown origin. Arch Intern Med 1995; 155;
198994.
Solis-Herruzo JA, Benita V, Morillas JD. Laparoscopy in fever of
unknown origin-study of seventy cases. Endoscopy 1981; 13: 20710.
Mitchell DP, Hanes TE, Hoyumpa AM Jr, Schenker S. Fever of
unknown origin: assessment of the value of percutaneous liver biopsy.
Arch Intern Med 1977; 137: 100104.
Knockaert DC, Dujardin KS, Bobbaers HJ. Long-term follow-up of
patients with undiagnosed fever of unknown origin. Arch Intern Med
1996; 156: 61820.

Maartens G, Willcox PA, Benatar SR. Miliary tuberculosis. Am J Med

1990; 89: 29196.
Raoult D, Fournier PE, Drancourt M, et al. Diagnosis of 22 new cases of
Bartonella endocarditis. Ann Intern Med 1996; 125: 64652.

Neoplasms
Ahmann DL, Kiely JM, Harrison EG Jr, Payne WS. Malignant lymphoma
of the spleen. Cancer 1966; 19: 46169.
Cronin RE, Kaehny WD, Miller PDl, et al. Renal cell carcinoma: unusual
systemic manifestations. Medicine 1976; 55: 291311.

Collagen vascular disease

Hamilton CR, Shelley WM, Tumulty PA. Giant cell arteritis. Medicine
1971; 50: 127.
Larson EB. Adult Stills disease. Medicine 1984; 63: 8291.

Miscellaneous
Aduan RP, Fauci AS, Dale DC, Herzberg JH, Wolff SM. Factitious fever
and self-induced infection. Ann Intern Med 1979; 90: 23042.
Mackowiak PA, LeMaistre CF. Drug fever: a critical appraisal of
conventional concepts. Ann Intern Med 1987; 106: 72833.

Vol 350 August 23, 1997