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Fever of unknown origin

Article  in  Clinical medicine (London, England) · June 2015

DOI: 10.7861/clinmedicine.15-3-280 · Source: PubMed

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 CME FEVER SYNDROMES Clinical Medicine 2015 Vol 15, No 3: 280–4

Fever of unknown origin

Authors: Catharina Mulders-Manders, A Anna SimonB and Chantal Bleeker-RoversC

More than 50 years after the first definition of fever of > temperature ≥38.3°C (101°F) on at least two occasions
> duration of illness ≥3 weeks or multiple febrile episodes in
ABSTRACT

unknown origin (FUO), it still remains a diagnostic challenge.

Evaluation starts with the identification of potential diagnostic ≥3 weeks
clues (PDCs), which should guide further investigations. In the > not immunocompromised (neutropenia for ≥1 week in
absence of PDCs a standardised diagnostic protocol should be the 3 months prior to the start of the fever; known HIV-
followed with PET-CT as the imaging technique of first choice. infection; known hypogammaglobulinemia or use of 10 mg
Even with a standardised protocol, in a large proportion of prednisone or equivalent for ≥2 weeks in the 3 months prior
patients from western countries the cause for FUO cannot to the start of the fever)
be identified. The treatment of FUO is guided by the final > Diagnosis uncertain despite thorough history-taking,
diagnosis, but when no cause is found, antipyretic drugs can be physical examination and the following investigations:
prescribed. Corticosteroids should be avoided in the absence of erythrocyte sedimentation rate or C-reactive protein,
a diagnosis, especially at an early stage. The prognosis of FUO haemoglobin, platelet count, leukocyte count and
is determined by the underlying cause. The majority of patients differentiation, electrolytes, creatinine, total protein,
with unexplained FUO will eventually show spontaneous protein electrophoresis, alkaline phosphatase, aspartate
remission of fever. We describe the definition, diagnostic aminotransferase, alanine aminotransferase, lactate
workup, causes and treatment of FUO. dehydrogenase, creatine kinase, antinuclear antibodies,
rheumatoid factor, microscopic urinalysis, ferritin, three
blood cultures, urine culture, chest X-ray, abdominal
ultrasonography and tuberculin skin test.
Definition and causes
Over 200 causes of FUO have been described in the literature.
Fever of unknown origin (FUO) was first defined by Petersdorf These causes can be subdivided in four categories: infections,
and Beeson in 1961, who defined FUO as body temperature malignancies, non-infectious inflammatory diseases (NIID, this
above 38.3°C (101°F) on three or more occasions and a duration group includes autoimmune and rheumatic diseases, vasculitis
of illness of at least three weeks, in which no diagnosis was made syndromes and granulomatous disorders) and miscellaneous
after one week of hospital admission.1 In the following years this causes.3, 6 Overall, uncommon presentations of common
definition was modified. Immunocompromised patients are now diseases account for most cases.
excluded,2 as these patients have other etiologies of FUO and In developing countries, infections are the major cause of
need a different therapeutic approach. To reflect the increasing FUO7–14, whereas in developed countries NIID account for
outpatient-based healthcare it was suggested to shorten the most cases.15–18 In several recent studies no cause could be
duration of investigation to three inpatient days or three found in a large proportion of patients (Table 1).3,5,19–21 Lower
outpatient visits.2 However, as investigations in three outpatient incidences of specific infections, such as tuberculosis and
visits and three inpatient days cannot be compared, different brucellosis, and differences in availability of modern imaging
causes of FUO will be found in admitted patients. Instead techniques, such as CT, MRI and FDG-PET/CT, may among
of using arbitrary quantitative time criteria, a quantitative others cause these differences.
criterion of obligatory investigations was implemented in the
definition.3–5 The current definition of FUO is:
Investigating FUO
Prior to any additional investigation, manipulation of the
thermometer needs to be excluded. Further diagnostic
evaluation of FUO starts with the identification of potential
Authors: Ainternal medicine resident, PhD student, Department of diagnostic clues (PDCs).3–5,22 PDCs are defined as all signs,
Internal Medicine, Radboud University Nijmegen Medical Center, symptoms and abnormalities pointing towards a possible
Nijmegen, The Netherlands; Binternist-infectious disease specialist, diagnosis. PDCs are identified by complete and repeated history
Department of Internal Medicine, Radboud University Nijmegen taking. The history should include information on previous
Medical Center, Nijmegen, The Netherlands; Cinternist-infectious medical history, drug use, family history, travel history, sexual
disease specialist, Department of Internal Medicine, Radboud history, unusual exposure due to occupation or hobbies, and
University Nijmegen Medical Center, Nijmegen, The Netherlands animal contacts. The search for PDCs is further carried out by a

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 CME Fever syndromes

Table 1. Characteristics and outcome of cohort studies on the etiology of FUO (≥100 patients published in
the last 10 years or from Western Europe).
Study and year Study characteristics Cause of FUO (% of total number of cases)
of publication Country Hospital Inclusion Design Patients, Infec- Malig- NIIDa Miscel- No
type period n tion nancy laneous diagnosis
Petersdorfb USA U 1952– P 100 36 19 19 29 7
19611 1957

de Kleijn The Netherlands U 1988– R 53 21 19 23 8 30

199515 1992

de Kleijn The Netherlands U 1992– P+M 167 26 13 24 8 30

19973 1994

Vanderschueren Belgium U 1990– P 185 11 10 18 8 53

200316 1999

Efstathiou Greece U 1992– P 112 30 11 33 5 21

201012 2000

Tabak Turkey U 1984– R 117 34 19 29 4 14

20049 2001

Chin Taiwan U 2001– P 94 57 9 7 9 18

200610 2002

Hu China U 2002– R 142 38 13 32 5 12

200828 2003

Kucukardali Turkey U 2003– P+M 154 34 14 31 5 16

200811 2004

Zenone France C 1999– P 144 23 10 26 15 26

200617 2005

Bleeker-Rovers The Netherlands U+C 2003– P+M 73 16 7 22 4 51

20075 2005

Hot France U 1995– R 280 11 20 27 9 33

200919 2005

Efstathiou Greece U 2001– P 100 35 10 36 3 16

201012 2007

Bandyopadhyay India U 2008– P 164 55 22 11 0 12

201113 2009

Mete Turkey U 2001– R 100 26 14 38 2 20

201214 2009

Pedersen Denmark U 2005– R 52 19 8 33 0 40

201220 2010

Vanderschueren Belgium U 2000– P 436 17 11 24 10 39

201421 2010

Naito Japan U+C 2011 R+M 121 23 11 31 12 23

201318
aGroup includes auto-immune and rheumatic diseases, vasculitis and granulomatous diseases3; bInterpretation difficult as these specific diagnostic groups are not
specifically mentioned, data therefore adapted from de Kleijn et al.3 C = community; FUO = fever of unknown origin; M = multicentre; NIID = non-infectious
inflammatory disease; P = prospective; R = retrospective; U = university.

careful physical examination with specific attention to the eyes, the skin and mucous membranes. Drug fever and factitious fever
temporal arteries, lymph nodes, liver and spleen, indicators of have to be excluded. Virtually all drugs can cause fever, even
previous invasive procedures, and a complete examination of after long-term use. As they may mask PDCs, all antibiotics and

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 CME Fever syndromes

Fever ≥38.3°C (101°F) AND illness ≥3 weeks AND no

known immunocompromised state

History and physical examinaon

Stop anbioc treatment and corcosteroids

Obligatory invesgaons: ESR or CRP, haemoglobin, platelet count, leukocyte count and
differenaon, electrolytes, creanine, total protein, protein electrophoresis, alkaline
phosphatase, ASAT, ALAT, LDH, creane kinase, annuclear anbodies, rheumatoid factor,
urinalysis, blood cultures (n=3), urine culture, chest X-ray, abdominal ultrasonography and
tuberculin skin test

Exclude manipulaon with thermometer

Stop or replace medicaon to exclude drug fever

PDCs present PDCs absent or misleading

Guided diagnosc tests Cryoglobulin and fundoscopy

FDG-PET/CT (or labelled leukocyte scingraphy or

DIAGNOSIS NO DIAGNOSIS galliumscan)

Scingraphy abnormal Scingraphy normal

Confirmaon of abnormality Repeat history and physical examinaon,

(eg biopsy, culture) PDC-driven invasive tesng

DIAGNOSIS NO DIAGNOSIS DIAGNOSIS NO DIAGNOSIS

Chest and abdominal CT,

temporal artery biopsy (≥55 years)

Fig 1. Flow chart of diagnosis of

fever of unknown origin. ALT =
DIAGNOSIS NO DIAGNOSIS alanine transaminase; AST =
aspartate aminotransferase; CRP =
C-reactive protein; ESR = erythro-
cyte sedimentation rate; LDH =
Stable condion: follow up Deterioraon: further lactate dehydrogenase; NSAIDs =
for new PDCs and consider diagnosc tests and consider non-steroidal anti-inflammatory
NSAID therapeuc trial drugs; PDCs = potential diagnostic
clues.

anti-inflammatory drugs have to be stopped at this stage. In PDCs, random microbiologic serology has a low diagnostic yield
virtually all cases, PDCs will be present.4,5 Further investigation and should therefore not be performed.3–5
should be guided by PDCs if present. Investigations should be When PDCs are absent or misleading, FUO should be further
selected based on local disease prevalence. In patients without evaluated following a standard diagnostic protocol (Fig 1).

282 © Royal College of Physicians 2015. All rights reserved.

CMJv15n3-CME-Simon.indd 282 11/05/15 11:03 AM

 CME Fever syndromes

Measurement of cryoglobulins and fundoscopic examination risk investigation, but false-negative results are often seen.26
should be performed in an early stage, because of the frequent FDG-PET/CT is a quick and non-invasive way to identify giant
absence of typical symptoms in diseases that can be found by cell arteritis.26 When FDG-PET/CT is normal, temporal artery
these investigations and their relatively low cost.4 When these biopsy should be performed in elderly patients with FUO even
tests do not lead to the fi nal diagnosis, one should proceed to in the absence of PDCs, as vasculitis limited to the temporal
whole body imaging,6 preferably with 18FDG-PET/CT.23 arteries may not be picked up by FDG-PET/CT due to the small
vessel diameter and high FDG-uptake in the brain.5,25–27
FDG-PET(/CT)
Bone marrow biopsy
FDG-PET is based on the increased uptake of FDG
(fluorodeoxyglucose) by activated inflammatory cells, which Although bone marrow aspiration can be diagnostic in some
occurs in infection, NIID and malignancy. In FUO, this non- cases,19 it is considered only helpful in FUO with PDCs for
specificity is advantageous, as all of these may cause FUO. a haematological disease or specific infection in the bone
The role of FDG-PET(/CT) in FUO was recently reviewed.24 marrow.4,5 Bone marrow biopsy is preferred over aspiration,
FDG-PET/CT is a non-invasive imaging technique with high because of its higher diagnostic yield. PDC-guided investigation
diagnostic yield and should therefore be performed early in and the use of FDG-PET/CT early in the diagnostic workup
the investigation of FUO. FDG-PET was helpful in 40% and of FUO will increase the diagnostic yield of bone marrow
FDG-PET/CT in 54% of cases. FDG-PET/CT is more specific, biopsy, as most bone marrow diseases that cause FUO will
as it allows exact anatomical location of an FDG-positive lesion. present with abnormalities at physical (eg lymphadenopathy,
Labeled leukocyte scintigraphy or gallium scintigraphy can be hepatosplenomegaly) or laboratory (eg cytopenia, elevated
used as alternatives when FDG-PET/CT is unavailable, but have LDH) examination, or lead to abnormal FDG-PET/CT findings
lower diagnostic yield.6,23,25 (in the case of lymphoma or metastatic tumours).5 Therefore,
bone marrow biopsy should not be performed in the absence of
PDCs for possible bone marrow diseases.
CT
The diagnostic yield of CT alone is lower than the yield of FDG- Treatment
PET/CT.5 This is partly because specific anatomical changes
may be absent in inflammation, particularly early in the illness, When all previously described investigations do not lead to the
and CT cannot distinguish active infection from residual diagnosis, further investigations should only be carried out
anatomical changes. when the patient deteriorates, or when new PDCs are identified
by repeated history taking and physical examination. In stable
patients without a diagnosis, non-steroidal anti-inflammatory
Temporal artery biopsy
drugs can be used as antipyretics.
The incidence of giant cell arteritis in FUO varies from When no cause for the fever is found and the patient
1% to over 10% in studies, and may become higher as our deteriorates despite extensive investigation, a drug trial should
populations age. Temporal artery biopsy is considered a low- be considered. Corticosteroids are an option, but they should
not be prescribed too early, as important diagnostic clues can
be altered or even disappear with steroid treatment, thereby
Key points delaying diagnosis and targeted specific therapy. In patients
with a suspected autoinflammatory disorder the interleukin-1
In developing countries infections remain the most common receptor antagonist, anakinra, can be tried. Remission of
cause of FUO, while non-infectious inflammatory diseases symptoms is expected within 24–48 hours. If anakinra is
or no diagnosis cause FUO in the majority of patients in ineffective after two weeks of treatment, a beneficial effect
developed countries. should not be expected and the drug should be stopped.

Potential diagnostic clues from history and physical

Prognosis
examination should guide diagnostic procedures in FUO.
The overall prognosis of FUO is determined by the underlying
In the absence of potential diagnostic clues, a standardised disease. In patients in whom no cause of FUO can be established,
diagnostic protocol with a major role for FDG-PET should be prognosis is generally good and mortality is low.21 Up to 75%
followed. of patients experience spontaneous remission of fever, although
this may take a long time.4,5,15,20 Treatment with NSAIDs or
When no cause for the fever is found, antipyretics can be used corticosteroids increases this proportion even further.5
as symptomatic treatment.
Conclusion
Most patients with FUO in whom no cause is identified show
More than 50 years after the first definition, FUO remains
spontaneous remission of fever.
a challenging diagnostic problem. With the development of
better diagnostic techniques, the cause of fever is often found
KEYWORDS: Fever of unknown origin, diagnosis, FDG-PET,
before three weeks of illness and therefore only more difficult to
infection, malignancy, connective tissue disease, systemic
diagnose cases meet the definition of FUO. The latest addition
autoinflammatory diseases, treatment ■
to the diagnostic protocol is early FDG-PET/CT, which has

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 CME Fever syndromes

a high diagnostic yield. In a substantial part of all cases, no 16 Vanderschueren S, Knockaert D, Adriaenssens T et al. From pro-
cause for the fever can be found. These patients have a good longed febrile illness to fever of unknown origin: the challenge
prognosis. ■ continues. Arch Intern Med 2003;163:1033–41.
17 Zenone T. Fever of unknown origin in adults: evaluation of
144 cases in a non-university hospital. Scand J Infect Dis
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Address for correspondence: Dr CM Mulders-Manders,
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Radboud University Medical Center, Department of Internal
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