Molecular Imaging of Fever of Unknown

Origin: An Update
Nick D. van Rijsewijk, MD,* Frank F.A. IJpma, MD, PhD,†
Marjan Wouthuyzen-Bakker, MD, PhD,z and Andor W.J.M. Glaudemans, MD, PhD*

18
F-FDG PET/CT, 67Ga-citrate and white blood cell (WBC) scintigraphy are molecular imag-
ing techniques currently used in the diagnostic workup of fever of unknown origin. How-
ever, it is unknown which technique fits which patient group best. A systematic literature
search has been performed for original articles regarding the use of molecular imaging in
fever of unknown origin. A total of 820 eligible studies were screened of which 63 articles
evaluating 5094 patients met the inclusion criteria. 18F-FDG PET/CT provided good diag-
nostic accuracy (with a weighted mean sensitivity, specificity, positive predicting value,
negative predictive value, accuracy and helpfulness of 84.4%, 61.8%, 80.7%, 67.8%,
76.3%, and 61.1%, respectively). Even within specific patient groups such as children,
elderly, patients with connective tissue diseases, patients on renal replacement therapy,
and HIV-infected patients, 18F-FDG PET/CT provided good diagnostic values. For 67Ga-cit-
rate scintigraphy, the weighted mean sensitivity, specificity, positive predictive value, nega-
tive predictive value, and helpfulness were 42.2%, 80.3%, 82.4%, 41.9%, and 42.2%,
respectively. WBC scintigraphy shows a weighted mean sensitivity, specificity, positive
predictive value, negative predictive value and accuracy of 73.5%, 86.3%, 79.1%, 82.4%,
and 79.5%, respectively. However, compared to 67Ga-citrate and WBC scintigraphy, signifi-
cantly more research has been performed using 18F-FDG PET/CT and 18F-FDG PET/CT has
the advantage of relatively short procedural duration; it is therefore the preferred molecular
diagnostic imaging technique. 67Ga-citrate and WBC scintigraphy can only be considered if
18
F-FDG PET/CT is not available.
Semin Nucl Med 53:4-17 © 2022 The Author(s). Published by Elsevier Inc. This is an open
access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Introduction body temperature that rises above 38.3°C two times or more,
2) persisting fever for at least 3 weeks or multiple febrile epi-

F ever of unknown origin (FUO) refers to a condition in

which the non-immunocompromised patient has 1) a
*Medical Imaging Center, Department of Nuclear Medicine and Molecular
Imaging, University of Groningen, University Medical Center Gronin-
gen, Groningen, The Netherlands.
y
Department of Trauma Surgery, University of Groningen, University
Medical Center Groningen, Groningen, The Netherlands.
z
Department of Medical Microbiology and Infection Prevention, University
of Groningen, University Medical Center Groningen, Groningen, The
Netherlands.
The authors declare that they have no known competing financial interests
or personal relationships that could have appeared to influence the work
reported in this paper.
Corresponding author: Nick D. van Rijsewijk, Medical Imaging Center,
Department of Nuclear Medicine and Molecular Imaging, University
Medical Center Groningen, Hanzeplein 1, Groningen, GZ 9713, The
Netherlands, +31 (0031) 50-3610146 E-mail: n.d.van.rijsewijk@umcg.nl
sodes in at least 3 weeks and 3) for which no explanation can
be found.1 When the criterion on temperature is unfulfilled,
but the patient does have raised inflammation parameters, it
is classified as inflammation of unknown origin (IUO).2
A mortality range from 6% till 33% has been reported
for FUO.3 The prognosis is mainly determined by the
underlying disease and diagnostic delay.4 There is a broad
range of causes (> 200) which can be classified into four
main categories: non-infectious inflammatory diseases,
infections, malignancies, and miscellaneous diseases.4,5
Hence, the workup of a patient with FUO starts with
identifying potential diagnostic clues through anamnesis
and physical examination, followed by laboratory investi-
gations and first-line medical imaging such as chest X-ray
and abdominal ultrasonography.6

4 https://doi.org/10.1053/j.semnuclmed.2022.07.002
0001-2998/© 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/)
Molecular Imaging of Fever of Unknown Origin: An Update
Conventional imaging methods, including computed
tomography (CT) and magnetic resonance imaging (MRI),
may provide information about anatomical abnormalities.7,8
For instance, CT of the chest and/or abdomen has the ability
to visualize lung nodules, lymphadenopathy and/or abscesses
and thus can be suggestive for malignancy or infection.8
However, these conventional imaging techniques are per-
formed only in a particular body part, and may not be able to
detect early stages of diseases or discriminate inflammation
from malignancies.7,8
Nuclear imaging techniques have the ability to detect met-
abolic changes in early stages of disease, but all of the avail-
able techniques have their own advantages and
disadvantages. A traditional nuclear total body imaging tech-
nique used in FUO is 67Ga-citrate scintigraphy. Gallium
accumulates in malignant cells and inflamed tissue,9 but the
uptake is nonspecific. Disadvantages of imaging with 67Ga
are the relatively high radiation burden, limited resolution
and prolonged procedural duration.8,10 However, because of
its proven utility in the diagnosis of FUO, it is still being
used in some hospitals.9
Another single photon emission computed tomography
(SPECT) modality is radiolabelled (111In or 99mTc) autolo-
gous white blood cells, which is especially useful when an
infectious cause is suspected.9 This imaging technique is very
specific for infections, but requires a laborious cell labelling
procedure and dual time point imaging.11 While depending
on accumulation of leukocytes, other origins of fever than
infections might be undiagnosed.8
Currently, 18F-fluorodeoxyglucose positron emission
tomography/computed tomography (18F-FDG PET/CT) is
considered the state-of-the-art whole body imaging method
in the diagnostic workup of FUO. This technique provides
good resolution, quantification methods and the ability of
whole-body imaging. Moreover, it became more accessible
and has a relatively short procedural duration (about 2
hours).8,10,11 Because of nonspecific 18F-FDG uptake, most
causes of FUO (eg, malignancy, infection, or inflammatory
(autoimmune) disease) can be visualized, since both malig-
nant cells and activated inflammatory cells are 18F-FDG
avid.1 However, often no distinction between inflammation,
infection and malignancy can be made and therefore further
diagnostics are often warranted.
To date, a comprehensive overview of clinical applications
of molecular imaging techniques in the diagnostic work-up
of FUO is lacking. In this review we will 1) present an over-
view of the diagnostic accuracy of FUO for different molecu-
lar imaging methods in the past two decades and 2) describe
the role of molecular imaging methods in different patient
groups. A short comparison of techniques will be provided
with the ultimate goal to determine which technique fits best
in which patient group.
Methods
The goal of this review was to determine the diagnostic value
of nuclear imaging techniques in FUO. The objective was to
5
provide an overview of the available techniques, to make a
short comparison of diagnostic values in different imaging
techniques and to unravel which technique fits which patient
group best.
A literature search in PubMed and Web of Science was
performed. In PubMed the following combination of MeSH
terms and single search terms were used: ("Fever of unknown
origin"[MeSH Terms] AND "radionuclide imaging"[MeSH
Terms]) OR ("Fever of unknown origin"[All Fields] AND
("PET"[All Fields] OR "nuclear medicine"[All Fields] OR
"nuclear imaging"[All Fields] OR "SPECT"[All Fields] OR "scinti-
graphy"[All Fields])). Web of Science was trawled with the
combination of “fever of unknown origin” and the single
search terms “nuclear medicine,” “nuclear imaging,” “scintig-
raphy,” “PET” or “SPECT.” The search period was limited to
January 1, 2000-December 31, 2021. Languages were
restricted to English, Dutch, and German.
Main inclusion criteria were original clinical studies
reporting on the contribution of nuclear imaging used in
diagnostics of FUO. Studies mentioning IUO and unex-
plained fever were also included as the definition of FUO is
not always met in clinical practice before referring to the
nuclear medicine department for further investigations.
There were no restrictions regarding the sample size. When
studies analysed PET, these were only included if the study
was performed using a combined PET/CT system as PET
only systems are not frequently used anymore. Reviews,
meta-analyses, conference/meeting abstracts, case series, and
case reports were excluded.
Initially, a screening of titles and abstracts according to the
inclusion and exclusion criteria was done. Next, full-text
assessment was performed. To ensure completeness of
papers, reference lists of selected articles were also cross-
checked for additional relevant studies.
The following data were extracted: first author, year, study
design, method of nuclear imaging, study population and
sample size, sensitivity, specificity, positive predictive value
(PPV), negative predictive value (NPV), and accuracy if
reported and otherwise calculated if absolute numbers were
available. Helpfulness, which is defined as the percentage of
nuclear imaging investigations directing to the clinical diag-
nosis, was also extracted. Regarding the focus of this review,
all information about specific patient groups and compari-
sons to other imaging techniques were also extracted.
Descriptive statistics were used to provide a comprehen-
sive overview of diagnostic accuracy and helpfulness in the
different nuclear imaging techniques and subpopulations.
Results
Using our search strategy, 1172 citations were identified.
After removing duplicates and screening of the title and
abstract, 91 references remained to be assessed in full text.
From these 91, 31 were excluded since a PET only camera
system (without CT component) was used, no patients with
FUO were analysed, or for other reasons. Additionally, three
studies were identified for inclusion based on the screening
6 N.D. van Rijsewijk et al.
of reference lists. A flow diagram of the study selection pro-
cess is shown in Figure 1.
Finally, 63 articles were included. An overview of the
selected studies is presented in Table 1. All included studies
were published in English. Ten of the selected studies were
prospectives and 54 retrospectives. The sample size varied
between 6 and 498 cases. Most of the studies included
patients with FUO, and some included patients with IUO as
well. Three studies evaluated patients with IUO only. The
most frequently investigated nuclear imaging technique was
18
F-FDG PET/CT (n = 55). Eleven studies addressed other
nuclear imaging methods including: 67Ga-scintigraphy
(n = 5), labelled white blood cells (n = 5) and 99mTc-UBI
(n = 1).
18
F-FDG PET/CT
In the 63 reviewed studies, the diagnostic value of 18F-FDG
PET/CT has been investigated in 36 and clinical helpfulness
has been evaluated in 42 studies. An overview is included in
Figure 2.
The sensitivity of 18F-FDG PET/CT in FUO varied between
34.5% and 100%, with a weighted mean of 84.4% (SD 12.3,
n = 3192) (Fig. 2). Studies including more than 200 partici-
pants demonstrate higher sensitivities.13,27,34,43 Buchrits
et al.13 observed a sensitivity of 88.7% in 303 FUO patients.
Figure 1 PRISMA flow diagram of systematic review search.
Wang et al.27 included 253 FUO and IUO patients and found
a sensitivity of 88.4%. In the prospective study of Sch€ onau
et al.,34 sensitivity was 91.1% including 240 participants.
Balink et al.,43 included 498 patients with FUO and IUO and
observed a sensitivity of 89%. All studies, except from three
studies,16,49,60 reported a sensitivity above 65%. The low
sensitivities found in these three studies can be attributed to
low frequencies of definitive diagnosis of FUO.
However, the variation in specificity was even broader
with a range from 0% to 100%. The weighted mean for spec-
ificity was 61.8% (SD 28.9, n = 3192) (Fig. 2). In the study
of Pelosi et al.,60 the specificity was zero, because methodo-
logically all normal 18F-FDG PET/CT scans were considered
as false negatives, which automatically also turned the nega-
tive predictive value to zero. Positive predictive values were
mostly above 65% with a weighted mean of 80.7% (SD 14.5,
n = 3123) (Fig. 2). Negative predictive values were also
diverse (range: 0%-100%, weighted mean: 67.8%, SD 20.4,
n = 2986) (Fig. 2).
The diagnostic accuracy of 18F-FDG PET/CT in the
reviewed studies ranged from 44% till 95.6%, with a
weighted mean of 76.3% (SD 13.8, n = 3059) (Fig. 2).
Helpfulness was evaluated in 42 studies (including 3183
patients) with a contribution of 18F-FDG PET/CT in diagno-
sis or management for FUO ranging from 21% to 99%, with
a weighted mean value of 61.1% (SD 22.1, n = 3183)
Molecular Imaging of Fever of Unknown Origin: An Update 7

Table 1 Overview of Studies (in Order of Publication Year) Evaluating Molecular Imaging Modalities in the Diagnostic Work-up of
FUO
Reference Study Design Imaging Modality Patients FUO/IUO
12 18
Bilici Salman et al. (2021) Retrospective F-FDG PET/CT 97 IUO
Buchrits et al. (2021)13 Retrospective 18
F-FDG PET/CT & diagnostic CT 303 FUO
Chen et al. (2021)14 Retrospective 18
F-FDG PET/CT 242 FUO / IUO
Das et al. (2021)15 Retrospective 18
F-FDG PET/CT 43 FUO
Kubota et al. (2021)16 Prospective 18
F-FDG PET/CT & 67Ga-citrate SPECT 91 / 92 FUO
Letertre et al. (2021)17 Retrospective 18
F-FDG PET/CT 39 FUO
Mahajna et al. (2021)18 Retrospective 18
F-FDG PET/CT 91 FUO
Mulders-Manders et al. (2021)19 Retrospective 18
F-FDG PET/CT 104 FUO / IUO
Torn e Cachot et al. (2021)20 Prospective 18
F-FDG PET/CT 32 FUO / IUO
Tsuzuki et al. (2021)21 Retrospective 18
F-FDG PET/CT 50 FUO / IUO
Tsuzuki et al. (2021)22 Retrospective 67
Ga-citrate SPECT/CT 27 FUO / IUO
Yadav et al. (2021)23 Prospective 18
F-FDG PET/CT 27 FUO
Georga et al. (2020)24 Retrospective 18
F-FDG PET/CT 50 FUO
Pijl et al. (2020)25 Retrospective 18
F-FDG PET/CT 110 FUO / FWS
Tavakoli et al. (2020)26 Retrospective 18
F-FDG PET/CT & wbMRI 6 FUO
Wang et al. (2020)27 Prospective 18
F-FDG PET/CT 253 FUO
Zhu et al. (2020)28 Retrospective 18
F-FDG PET/CT 89 FUO / IUO / other
Lawal et al. (2019)29 Retrospective 18
F-FDG PET/CT 46 FUO
Wang et al. (2019)30 Retrospective 18
F-FDG PET/CT 376 FUO / IUO
Abdelrahman et al. (2018)31 Prospective 18
F-FDG PET/CT 27 FUO
Garcia-Vincente et al. (2018)32 Retrospective 18
F-FDG PET/CT 67 FUO / IUO
Kim et al. (2018)33 Retrospective 18
F-FDG PET/CT 8 FUO
Sch€ onau et al. (2018)34 Prospective 18
F-FDG PET/CT 240 FUO / IUO / other
Serrano Vicente et al. (2018)35 Retrospective 67
Ga-citrate SPECT/CT 57 FSUO
Wang et al. (2018)36 Retrospective 18
F-FDG PET/CT 14 Fever
Hung et al. (2017)37 Prospective 18
F-FDG PET/CT & 67Ga-citrate SPECT/CT 58 FUO
Tek Chand et al. (2017)38 Retrospective 18
F-FDG PET/CT 20 FUO
Bouter et al. (2016)39 Retrospective 18
F-FDG PET/CT 72 IUO / fever
Chang et al. (2016) 40 Retrospective 18
F-FDG PET/CT 19 FUO
Pereira et al. (2016)41 Retrospective 18
F-FDG PET/CT 76 FUO
Balink et al. (2015)42 Retrospective 18
F-FDG PET/CT 46 IUO
Balink et al. (2015)43 Retrospective 18
F-FDG PET/CT 498 FUO / IUO
Gafter-Gvili et al. (2015)44 Retrospective 18
F-FDG PET/CT 112 FUO
Yang et al. (2015)45 Retrospective 18
F-FDG PET/CT 175 FUO
Blokhuis et al. (2014)46 Retrospective 18
F-FDG PET/CT 28 + 11 FUO / fever
Balink et al. (2014)47 Retrospective 18
F-FDG PET/CT 140 IUO
Buch-Olsen et al. (2014)48 Retrospective 18
F-FDG PET/CT 58 FUO
Robine et al. (2014)49 Retrospective 18
F-FDG PET/CT 48 FUO
Sheng et al. (2014)50 Retrospective 18
F-FDG PET/CT 73 FUO
Tokmak et al. (2014)51 Retrospective 18
F-FDG PET/CT 25 FUO
Manohar et al. (2013)52 Retrospective 18
F-FDG PET/CT 103 FUO
Martin et al. (2013)53 Prospective 18
F-FDG PET/CT 30 FUO
Becerra Nakayo et al. (2012)54 Retrospective 18
F-FDG PET/CT 20 FUO
Crouzet et al. (2012)55 Retrospective 18
F-FDG PET/CT 79 FUO
Kim et al. (2012)56 Retrospective 18
F-FDG PET/CT 48 FUO
Pedersen et al. (2012)57 Retrospective 18
F-FDG PET/CT 22 FUO
Seshadri et al. (2012)58 Prospective 111
In-labelled leucocyte scintigraphy 23 FUO
Erg€ul et al. (2011)59 Retrospective 18
F-FDG PET/CT 24 FUO
Pelosi et al. (2011)60 Retrospective 18
F-FDG PET/CT 24 FUO
Sheng et al. (2011)61 Retrospective 18
F-FDG PET/CT 48 FUO
Federici et al. (2010)62 Retrospective 18
F-FDG PET/CT 14 FUO / UPIS
Ferda et al. (2010)63 Retrospective 18
F-FDG PET/CT 48 FUO
Jasper et al. (2010)64 Retrospective 18
F-FDG PET/CT 17 FUO
Kei et al. (2010)65 Retrospective 18
F-FDG PET/CT 12 FUO
Sep ulveda-M endez et al. (2010)66 Retrospective 99m
Tc-UBI 207 FUO / fever
Balink et al. (2009)67 Retrospective 18
F-FDG PET/CT 68 FUO
Castaigne et al. (2009)68 Retrospective 18
F-FDG PET/CT 10 FUO
8 N.D. van Rijsewijk et al.

Table 1 (Continued )
Reference Study Design Imaging Modality Patients FUO/IUO

Keidar et al. (2008)69 Retrospective 18

F-FDG PET/CT 48 FUO
Seshadri et al. (2008)70 Retrospective 111
In-labelled leucocyte scintigraphy 61 FUO
Gutfilen et al. (2006)71 Retrospective 99m
Tc-mononuclear leukocyte scintigraphy 87 FUO
Habib et al. (2004)72 Retrospective 67
Ga-citrate scintigraphy 102 FUO
Kjaer et al. (2004) 73 Prospective 111
In-granulocyte scintigraphy 19 FUO
Kjaer et al. (2002)74 Retrospective 111
In-granulocyte scintigraphy 31 FUO
Abbreviations: FUO, fever of unknown origin; IUO, inflammation of unknown origin; UPIS, unexplained prolonged inflammatory syndrome;
FSUO, febrile syndromes of unknown origin; FWS, fever without source; wbMRI, whole body magnetic resonance imaging.

(Fig. 2). The broad range can be clarified by differences in
definition of helpfulness. Some studies considered only true
positives to be helpful, while other studies considered true
positives and true negatives to be helpful. Other studies men-
tioned 18F-FDG PET/CT as helpful when it changed clinical
management.
Specific Patient Groups
Specific patient groups were analysed in eleven of the
reviewed studies. Children were the most investigated spe-
cific patient group (five studies). Two studies were per-
formed in patients with end-stage renal disease and another
two focused on HIV-infected patients. Single studies were

Figure 2 An overview of the diagnostic values and helpfulness of 18F-FDG PET/CT in the diagnostic workup of FUO.
The whiskers of this boxplot are set at 10% and 90%, weighted means are indicated with blue dots. The weighted
mean sensitivity, specificity, PPV, NPV, accuracy, and helpfulness are 84.4% (n = 3192), 61.8% (n = 3192), 80.7%
(n = 3123), 67.8% (n = 2986), 76.3% (n = 3059), and 61.1% (n = 3183), respectively. Median values for sensitivity,
specificity, PPV, NPV, accuracy, and helpfulness are 86.5% (IQR: 77.5%-92.1%, n = 36), 66.9% (IQR: 34.1%-82.7%,
n = 36), 83.0% (IQR: 67.0%-93.0%, n = 35), 67.0% (IQR: 50.0%-83.1%, n = 33), 71.5% (IQR: 62.9%-88.7%, n = 33)
and 60% (IQR: 45.8%-69.3%, n = 42), respectively.12-21,23-25,27-32,34,36-41,43,44,46-52,54-57,59-63,65,67-69 Abbreviations:
PPV, positive predictive value; NPV, negative predictive value.
Molecular Imaging of Fever of Unknown Origin: An Update 9

Table 2 Observed Diagnostic Accuracy for 18F-FDG PET/CT in Studies Focusing on Children
Number of Sensitivity Specificity PPV NPV Clinical
Study Subpopulation Participants (%) (%) (%) (%) Impact (%)

Pijl et al. (2020)25 FUO & FWS 110 86 79 84 81 53

Jasper et al. (2010)64 FUO 17 NR NR NR NR 41
Blokhuis et al. (2014)46 FUO 28 80 78 67 88 29
Unexplained 11 78 67 88 50 55
fever in immu-
nocompromised
children
Wang et al. (2018)36 Immunocompro- 14 NR NR NR NR 79
mised children
with prolonged
or recurrent
fever
Chang et al. (2016)40 Critically ill with 19 88 67 93 50 84
FUO
Abbreviations: FWS, fever without source; NR, not reported.

performed in elderly patients and patients with connective
tissue diseases.
Children. Seven of the reviewed studies included children
(age < 18 years), with a primary focus on children in five of
them. Two studies included both PET and hybrid PET/CT
imaging and provided limited segregated information for
18
F-FDG PET/CT. All of the included studies focusing on
children had been performed retrospectively in single-institu-
tions and therefore might be influenced by selection bias.
Except for the study of Pijl et al.,25 only a limited number of
patients (<30) have been included in these studies. How-
ever, all studies provide evidence for 18F-FDG PET/CT to be
a valuable tool for investigation and management in children
with FUO. The weighted mean sensitivity, specificity, PPV,
NPV and clinical impact were 84.7% (n = 168), 67.7%
(n = 168), 82.4% (n = 168), 76.6% (n = 168), and 53.5%
(n = 199), respectively. Diagnostic values are enclosed in
Table 2.
Pijl et al.25 evaluated 110 children with FUO and IUO in
which 18F-FDG PET/CT identified the definite cause of fever
in 48%. Both true positive (53/110, 48%) and true negative
rates (38/110, 35%) were high in this study and resulted to
good diagnostic values. The sensitivity, specificity, PPV and
NPV were 86%, 79%, 84%, and 81%, respectively. In 53%,
the 18F-FDG PET/CT resulted in a change in therapy, such as
switching antibiotics or starting immunosuppressive treat-
ment, with true positive cases three times more likely leading
to a change in treatment than patients with true negative
results. Hence, 18F-FDG PET/CT was found useful in the
management of FUO in paediatrics.25
Wang et al.36 studied fourteen children, immunocompro-
mised due to immunosuppressive therapy for malignancy,
aplastic anaemia or hematopoietic stem-cell transplantation,
with prolonged or recurrent fever. Although a prolonged
time between both fever onset and conventional imaging and
18
F-FDG PET/CT was reported, 18F-FDG PET/CT detected
seven more sites of infection or inflammation than
conventional CT and sustained a clinical impact in 79% of all
cases with alterations of antimicrobials in 64%. Referrals to
other medical specialists were made in 36%, which resulted
in a final diagnosis or a change in clinical management.36
Chang et al.40 demonstrated that 18F-FDG PET/CT was
clinically beneficial in 84% of all cases (n = 19) for evaluation
of FUO in critically ill children with complex underlying dis-
eases, while it was not contributory in only 16%. However,
the detection of the source of fever in these patients is often
very challenging, not only due to intrinsic factors such as the
heterogeneity of the clinical conditions, complicated underly-
ing diseases and the possibility of iatrogenic causes of fever
(eg, drug-induced fever), but also because of clinical and
logistic difficulties in an ICU setting.40
Jasper et al.64 reviewed seventeen 18F-FDG PET/CT scans
in children with FUO as part of a combined PET and PET/
CT paediatric case-mix study of FUO and unexplained signs
of inflammation. 18F-FDG PET/CT was considered helpful in
41% of FUO cases, because they excluded differential diag-
noses or revealed a focus.64 Since it was a mixed PET and
PET/CT study, no diagnostic accuracies were given and no
further data were presented solely for 18F-FDG PET/CT.
Blokhuis et al.46 investigated PET and PET/CT in juvenile
patients with FUO or unexplained fever during immune sup-
pression. A total of 28 18F-FDG PET/CT scans were per-
formed for investigating FUO. The sensitivity, specificity,
PPV, and NPV were 80%, 78%, 67%, and 88%, respectively.
In eleven 18F-FDG PET/CT scans made for unexplained fever
during immune suppression, the sensitivity, specificity, PPV
and NPV were 78%, 67%, 88%, and 50% respectively. For
this last juvenile patient group, the criterion of >3 weeks of
fever to diagnose FUO was unfulfilled, since they required
rapid diagnosis due to a substantial risk of rapid deteriora-
tion. Despite the fact that Blokhuis et al. only considered true
positive results as helpful, it is remarkable that within the
FUO patient group the reported clinical helpfulness of 18F-
FDG PET/CT was considerably lower (8/28, 29%) than in
the patient group with unexplained fever during immune
10 N.D. van Rijsewijk et al.

suppression (6/11, 55%).46 Because the time criterion for
FUO was not met in the latter group, this may be indicative
of a higher helpfulness in shorter diagnostic time frames.
A clinical example of the use of a 18F-FDG PET/CT scan in
a child is shown in Figure 3.
Elderly. One unique study explicitly focused on FUO in
older adults (60 years and above). Yadav et al.23 included a
total of 51 patients in this study with a median age of 64 years
(range from 60 till 92 years). Although the primary aim of the
study was not to discuss medical imaging in these elderly
with FUO, 18F-FDG PET/CT was performed in 27 patients
and seventeen of them contributed to diagnosis, which repre-
sented a diagnostic utility of 63%. In twenty cases, 18F-FDG
PET/CT was performed after contrast enhanced CT of chest
and abdomen, in which a different potential diagnostic was
noticed in two cases (10%).23
Connective Tissue Disease. Chen et al.14 retrospectively stud-
ied the diagnostic value of 18F-FDG PET/CT in patients with
connective tissue disease suffering from FUO (n = 205) or
IUO (n = 37). A significant percentage showed positive find-
ings on 18F-FDG PET/CT (98%) and therapy alterations were
made in 87%. Inflammatory foci with 18F-FDG uptake were
found in 67% even before significant structural changes
could be seen. The uptake patterns were corresponding with
various connective tissue diseases. Moreover, in 33% of all
patients, the 18F-FDG PET/CT was directly indicative for spe-
cific connective tissue disease such as systemic vasculitis,
rheumatoid arthritis and idiopathic inflammatory myopa-
thies. Nonspecific abnormal uptake, characterized as dif-
fusely increased 18F-FDG uptake in spleen and bone marrow
and along with reactive lymph nodes, was found in 31%.14
End Stage Renal Disease. Two of the reviewed articles evalu-
ated the use of 18F-FDG PET/CT in patients with end-stage
renal disease. In India, Kalawat et al.38 performed a retro-
spective study including twenty patients on renal replace-
ment therapy (18 haemodialysis, 2 peritoneal dialysis) who
underwent whole body imaging with 18F-FDG PET/CT in
the diagnostic workup of FUO. Fifteen scans showed foci
with increased uptake, while five scans were negative. The
principal cause of fever (75%) was tuberculosis, due to the
prevalence of tuberculosis in the general regional population.
In this study, tuberculosis was detected with 18F-FDG PET/
CT in ten of the 15 positive scans as cause of FUO. Also,
three negative scans contributed to the diagnosis of tubercu-
losis. Other causes of FUO were osteomyelitis, malaria, renal
abscess and not further specified high uptake in the caecum.
Finally, in 19 out of 20 patients in this study, treatment for
fever changed after performing a 18F-FDG PET/CT.38
The second study by Lawal et al.29 is also a retrospective
study, in which the diagnostic utility of 18F-FDG PET/CT
was investigated in 46 patients on renal function

Figure 3 A 13-year-old boy was referred to the hospital with multiple febrile episodes (up to 39.5°C) during the last 2
weeks. He was not feeling well, was very tired and had no appetite. His medical history included a liver transplantation
at the age of 10. During the hospital stay, his C-reactive protein levels were increasing from 36 to 91 mg/L in 1 week
for which no explanation could be found. 18F-FDG PET/CT revealed focal intense tracer uptake in the distal part of the
biliary stent (middle) and intense tracer uptake along the biliary stent intrahepatically (upper right), which is connected
to a homogeneous tracer collection in the right subdiaphragmatic region (middle and lower right). Meropenem was
started and the biliary stent was surgically removed 2 weeks after the PET/CT scan.
Molecular Imaging of Fever of Unknown Origin: An Update 11

replacement therapy (21 haemodialysis, 8 peritoneal dialy-
sis and 17 renal transplants). Although all patients were
already being treated with empirical antibiotic therapy at
the time of imaging, 29 scans still showed at least one focus
of increased uptake, while 17 scans turned out to be nega-
tive. In 22 patients with a positive scan, the cause of fever
was diagnosed at the site of increased uptake confirmed by
biopsy and microbial culture, and always turned out to be
an infection, thus 18F-FDG PET/CT was considered helpful
in the diagnosis of FUO in 48%.29
A clinical example of the use of a 18F-FDG PET/CT scan in
a patient after kidney transplantations is shown in Figure 4.
HIV-infected Patients. Martin et al.53 prospectively studied
the performance of 18F-FDG PET/CT in 20 HIV-infected
patients with FUO and compared them to ten HIV-infected
high viraemic patients without FUO. High viraemic status
did not interfere with correct interpretation of 18F-FDG PET/
CT in this study. Despite these limited included patients,
18
F-FDG PET/CT of asymptomatic patients showed different
uptake patterns compared to those from patients with FUO:
many of the asymptomatic patients showed hypermetabolic
peripheral lymph nodes in the cervical and axillary areas
(86%) and in the iliac and inguinal areas (>50%), while in
patients with FUO central hypermetabolic lymph nodes were

Figure 4 A 65-year-old woman was referred for 18F-FDG PET/CT for the investigation of inflammation of unknown ori-
gin with high C-reactive protein levels (68-74 mg/L) ongoing for several weeks. There was no fever, nor any potential
diagnostic clues. The medical history included two kidney transplants, of which the last one was performed 9 months
ago. Besides physiological uptake, the PET/CT scan showed increased 18F-FDG uptake at the right shoulder (DD: syno-
vitis or arthritis) and recent fractures of the left 6th costa and the right pubis bone. Furthermore, it revealed multiple
abscesses or infected hematomas in the left gluteal musculature (lower right) and intense tracer accumulation around
the left total hip prosthesis (upper right) which was placed 4 years ago. A low-grade infection of the total hip prosthesis
was diagnosed after revision surgery.
12
observed. 18F-FDG PET/CT contributed to the diagnosis (eg,
tuberculosis, nontuberculous mycobacteriosis and lym-
phoma) or exclusion of focal aetiology in 80% in the HIV-
infected patients with FUO. Moreover, central lymph node
biopsies guided by 18F-FDG PET/CT were always diagnostic
in these patients with FUO.53 Earlier, another study includ-
ing ten HIV-infected patients with FUO was retrospectively
performed by the same research group.68 In all cases, abnor-
mal 18F-FDG PET/CT directed diagnosis by targeting lymph
node biopsy, sputum culture or bronchoalveolar lavage.
Moreover, 18F-FDG PET/CT demonstrated more extensive
disease than conventional imaging, particularly in subdiaph-
ragmatic regions. True positives were considered helpful
only and represented 90% of all scans.68
67
Ga-citrate Scintigraphy
Five of the included studies investigated the use of 67Ga-cit-
rate scintigraphy in FUO.16,22,35,37,72 An overview is pre-
sented in Table 3. A total of 336 patients were investigated.
The weighted mean sensitivity, specificity, PPV, NPV, and
helpfulness in FUO diagnosis were 42.2% (n = 207), 80.3%
(n = 207), 82.4% (n = 207), 41.9% (n = 115), and 42.2%
(n = 279) respectively.
The two most recent ones were published in 2021, of
which one was performed prospectively. In this particular
study, Kubota et al.16 investigated 67Ga-citrate SPECT in 92
patients and compared it to 18F-FDG PET/CT in 91 patients.
67
Ga-citrate SPECT contributed to diagnosis in 57% of cases
and led to therapy change in 21% of cases. Sensitivity, speci-
ficity, PPV, and accuracy were 25%, 72%, 71%, and 38%,
respectively. Another prospective study comparing 18F-FDG
PET/CT to 67Ga-citrate scintigraphy performed by Hung
et al.,37 published in 2017, included 58 patients and showed
satisfactory results for 67Ga-citrate SPECT/CT with a clinical
contribution to diagnosis of 55% of all scans. Sensitivity,
specificity, PPV, and NPV were 45%, 81%, 86%, and 36%,
respectively.37 The comparative results of 67Ga-citrate SPECT
with 18F-FDG PET/CT will be mentioned later.
Tsuzuki et al.22 investigated the diagnostic yield and clini-
cal efficacy of 67Ga-citrate SPECT/CT in a retrospective study
including 27 patients (17 FUO and 10 IUO). Prior to 67Ga-
citrate SPECT/CT, all patients underwent an abdominal and
chest CT without contrast. In none of these patients the cause
of FUO was found. However, additional 67Ga-citrate SPECT/
CT contributed in diagnosing the cause of FUO or IUO in
Table 3 Studies Investigating the Use of 67Ga-citrate Scintigraphy in the Diagnostic Workup of FUO
Number of Sensitivity
Study Participants (%)
Kubota et al. (2021)16 92 25
Hung et al. (2017)37 58 45
Tsuzuki et al. (2021)22 27 NR
Serrano Vincente (2018)35 57 67
Habib et al. (2004)72 102 NR
Abbreviations: NR, Not reported.
N.D. van Rijsewijk et al.
eight patients, which represented a diagnostic yield of 30%.
For example, 67Ga-citrate SPECT/CT directed to the diagno-
sis of diffuse large B-cell lymphoma, giant cell arteritis, and
sarcoidosis. The diagnostic yield did not differ between FUO
or IUO in this study. When spontaneous and sustained
remission with a negative scan was also assessed as clinically
relevant, the clinical efficacy raised to 44% in all patients.
However, only in the IUO patient group the clinical efficacy
incremented (from 30% to 70%).22
Habib et al.72 evaluated the utility of 67Ga-citrate scintigra-
phy in FUO in 102 patients. A total of 40% of the scans were
considered abnormal, and nearly half of them contributed to
diagnosis. Thus, in a total of 21 patients (20.5%), 67Ga-cit-
rate SPECT (without CT) was considered helpful. In nineteen
of them, the findings were congruent with those obtained by
CT, ultrasound, physical examination, and/or other evaluat-
ing methods. Only two of all scans were marked as signifi-
cantly contributive towards the final diagnosis, since
diagnosis could be made solely on the result of 67Ga-citrate
scintigraphy.72
In febrile syndromes of unknown origin, patients who did
not fulfil the full FUO criteria, Serrano Vincente et al.35
found a sensitivity and specificity for 67Ga-citrate SPECT/CT
of 67% and 93%, respectively. The diagnostic accuracy was
73%. The positive and negative predictive values were 97%
and 48%, respectively. In only one case (1.8%), CT showed
a focus without tracer uptake.35
White Blood Cell Scintigraphy
The use of WBC scintigraphy was exclusively evaluated in
five studies,58,70,71,73,74 performed by three research groups.
All studies were published at least ten years ago mostly using
WBC labelled with 111In. Two of the reviewed studies com-
pared WBC scintigraphy with 18F-FDG PET (without
CT).58,73 A total of 214 WBC scans were investigated. The
weighted mean sensitivity, specificity, PPV, NPV, and accu-
racy were 73.5%, 86.3%, 79.1%, 82.4%, and 79.5%, respec-
tively. An overview of the included studies is presented in
Table 4.
Kjaer and Lebech 74 retrospectively studied the diagnostic
value of 111In-granulocyte scintigraphy in 31 patients with
fever of unknown origin. Sensitivity, specificity, PPV, NPV
and accuracy were 75%, 83%, 60%, 90%, and 81%, respec-
tively.74 Two years later, Kjaer et al.73 published a prospec-
tive study comparing 18F-FDG PET (without CT) to 111In-
Specificity PPV NPV Helpfulness
(%) (%) (%) (%)
72 71 NR 57
81 86 36 55
NR NR NR 44
93 97 48 NR
NR NR NR 21
Molecular Imaging of Fever of Unknown Origin: An Update 13

Table 4 Studies Investigating the Use of WBC Scintigraphy in the Diagnostic Workup of FUO
No. Sensitivity Specificity PPV NPV Accuracy
Study Technique Patients (%) (%) (%) (%) (%)

Kjaer et al. (2002)74 111

In-granulocyte 31 75 83 60 90 81
Kjaer et al. (2004)73 111
In-granulocyte 19 71 92 85 85 84
Seshadri et al. (2012)58 111
In-labelled leucocyte 23 20 100 100 40 48
Gutfilen et al. (2006)71 99m
Tc-mononuclear leukocyte 87 96 92 94 95 94
Seshadri et al. (2008)70 111
In-labelled leucocyte 54 60 71 55 75 67

granulocyte scintigraphy in 19 patients. In this study, 18F-
FDG PET had a sensitivity and specificity of 50% and 46%
respectively, while granulocyte scintigraphy had a sensitivity
and specificity of 71% and 92% respectively. Moreover, PPV
and NPV were higher in granulocyte scintigraphy with both
85%, compared to 30% and 67% respectively for 18F-FDG
PET.73
In contrast, another study published in 2012 by Seshadri
et al.58 found superiority of 18F-FDG PET (without CT)
when making a comparison of 18F-FDG PET to 111In-labelled
leucocyte scintigraphy in 23 patients. Abnormal tracer
uptake was observed in only three patients (13%) with WBC
scintigraphy, while 18F-FDG PET showed abnormal tracer
uptake in 14 patients (61%) of which two were false posi-
tives. All foci found on WBC scintigraphy were also detected
by 18F-FDG PET and were of infectious origin, however 18F-
FDG PET detected three more infectious foci. WBC scintigra-
phy did not detect noninfectious inflammation and malig-
nancy as expected, while 18F-FDG PET was contributory in
six out of nine diagnosis of noninfectious inflammation and
malignancy. Therefore, the overall diagnostic contribution of
18
F-FDG PET in FUO was superior with a sensitivity, speci-
ficity, PPV and NPV of 86%, 78%, 86%, and 78% respec-
tively compared to those of WBC scintigraphy with a
sensitivity, specificity, PPV, and NPV of 20%, 100%, 100%,
and 40% respectively.58
Gutfilen et al.71 aimed to determine the overall diagnostic
accuracy of 99mTc-mononuclear leukocyte scintigraphy in
the diagnostic workup of FUO. This study included 87
patients, of which 66 were suspected to have an infection
(like endocarditis and osteomyelitis) and 21 patients present-
ing without any potential diagnostic clue. The sensitivity,
specificity, PPV, NPV, and accuracy were 96%, 92%, 94%,
95%, and 94%, respectively. Contribution to diagnosis in
abnormal scintigraphy results was 45 out of 49 and in nor-
mal scintigraphy results 36 out of 38, thus an overall contri-
bution to diagnosis of 93%.71 However, these high
diagnostic values were influenced by the high a priori chance
of infection.
Diagnostic values for 111In-labelled leucocyte scintigraphy
were investigated by Seshadri et al.70 in 54 patients, of whom
28 were in a postoperative period. In the general patient
group, sensitivity, specificity, PPV, and NPV were 60%, 71%,
55%, and 75% respectively, while in the subgroup of post-
operative (< 2 months) patients the specificity and PPV were
much higher with 82% and 83% respectively. However, the
aetiology pattern of FUO was not reported in the postopera-
tive group.70
99m
Tc-UBI
In 2010, one study was published investigating 99mTc-UBI (a
synthetic radiolabelled antimicrobial peptide) in 207 scans
from 196 patients with FUO.66 In this study, patients were
referred for the investigation of FUO, but a suspected diagno-
sis had been formulated beforehand in many patients (eg,
osteomyelitis in 69%, diabetic foot in 16%, and infected
prosthesis in 14%). High sensitivity and specificity were
noticed for detecting infectious foci, with 97.5% and 95.4%
respectively. Comparing the bacterial cultures with the
molecular imaging, there was an agreement of 96.6%.66
However, as far as we know, this imaging technique is not
used in clinical routine.
Comparison of Imaging Techniques
18
F-FDG PET/CT Compared to 67Ga-citrate
Scintigraphy
As previously mentioned, Kubota et al.16 compared 18F-FDG
PET/CT to 67Ga-citrate scintigraphy. A total of 142 positive
findings was reported for 18F-FDG PET/CT compared to 60
for 67Ga-citrate SPECT. This study showed a superior sensi-
tivity and clinical impact for 18F-FDG PET/CT to 67Ga-citrate
SPECT. The clinical impact of 67Ga-citrate SPECT was 57%
while it was 91% for 18F-FDG PET/CT and the sensitivity of
67
Ga-citrate SPECT was only 25%, while it was 45% for 18F-
FDG PET/CT. Treatment plans have been changed in 21%
based on 67Ga-citrate SPECT, while it was 33% based on
18
F-FDG PET/CT. However, nonspecific uptake (false-posi-
tives) caused lower specificity for 18F-FDG PET/CT (40%)
compared to 67Ga-citrate SPECT (72%).16
Compared to 67Ga-citrate SPECT/CT, Hung et al.37 also
found a significantly higher sensitivity (79% for 18F-FDG
PET/CT, 45% for 67Ga-citrate SPECT/CT) and clinical contri-
bution (72% for 18F-FDG PET/CT, 55% for 67Ga SPECT/
CT) in favour of 18F-FDG PET/CT. Regarding 18F-FDG PET/
CT, a high false positive rate of 44% was observed, while a
high false negative rate of 55% was observed for 67Ga-citrate
SPECT/CT. In patients with infections, non-infectious
inflammatory diseases and malignancies, all 67Ga-avid lesions
were also visualized using 18F-FDG PET/CT. However, addi-
tional foci were discovered with 18F-FDG PET/CT. For exam-
ple, out of a total of 23 patients with FUO due to infection,
both 18F-FDG PET/CT and 67Ga-citrate SPECT/CT correctly
identified a focus in eight patients, yet another nine patients
with infectious foci were found using 18F-FDG PET/CT.
However, this contrast was less in patients with an
14
underlying malignancy (n = 10), in which 67Ga-citrate
SPECT/CT revealed the focus in eight patients and only one
more 18F-FDG PET/CT scan showed a missed focus. This
particular patient was definitively diagnosed with neuroen-
docrine cancer of an unknown primary site.37
18
F-FDG PET/CT Compared to Diagnostic CT
A comparison of 18F-FDG PET/CT with diagnostic CT was
retrospectively performed by Buchrits et al.,13 in which the
full PET/CT examination record as well as the diagnostic CT
component only were interpreted separately in 303 cases.
Sensitivity and specificity for CT were 75% and 90%, respec-
tively. In 68% of all cases, CT scans were contrast enhanced.
Sensitivity and specificity for 18F-FDG PET/CT were 89%
and 82% respectively and these numbers did not differ sig-
nificantly when the CT component was contrast enhanced or
not. In conclusion, 18F-FDG PET/CT was found superior
with a higher sensitivity, but lower specificity compared to
diagnostic CT. Furthermore, PET/CT was necessary for diag-
nosis in 26% of all cases and it did not make a difference if
CT was performed with or without iodine contrast.13
18
F-FDG PET/CT Compared to Whole Body MRI
Tavakoli et al.26 retrospectively investigated whole body MRI
in the diagnostic workup of FUO in 24 patients. In general,
79% of whole-body MRI scans was considered abnormal, the
detection rate of inflammatory foci was 71% and a focus
could be found in 46% based on whole body MRI only with
negative other conventional diagnostic tests including chest
X-ray, ultrasound, and CT. However, in this study only six
patients also underwent 18F-FDG PET/CT examination. Both
methods found similar inflammatory foci in four of them,
and no foci were found in the other two patients, not on 18F-
FDG PET/CT nor by whole body MRI.26
Discussion
In the past 2 decades, the most investigated nuclear imaging
methods in the diagnostic workup of FUO are mostly 18F-
FDG PET/CT, and occasionally 67Ga-citrate scintigraphy and
WBC scintigraphy. Specifically for the latter two techniques,
some studies mention the regional availability of the nuclear
imaging techniques as a critical factor for investigating a par-
ticular nuclear imaging modality,35,71 while others mention
the covering by the health insurances as a critical factor.16,22
18
F-FDG PET/CT is currently the state-of-the-art nuclear
imaging technique in the workup of FUO and this is repre-
sented by the substantial number of performed studies.
Regarding diagnostic values, weighted mean sensitivity, spec-
ificity, PPV, NPV, accuracy, and helpfulness were determined
as 84.4%, 61.8%, 80.7%, 67.8%, 76.3%, and 61.1%. The
large variability between the studies is presumably due to the
heterogeneity of the patient populations, variations in sample
size, used definitions, and the study settings. Also, currently,
there is no specific guideline on the timing of the use of 18F-
FDG PET/CT in fever of unknown origin (and by extension
inflammation of unknown origin). Hence, for each
N.D. van Rijsewijk et al.
retrospective study, the various referring circumstances (eg,
18
F-FDG PET/CT as a second- or third line diagnostic proce-
dure and prior diagnostic investigations) make it difficult to
compare the results.
Taking a closer look at other specific patient groups, stud-
ies on the diagnostic accuracy of 18F-FDG PET/CT were per-
formed in children, elderly, patients with connective tissue
diseases, patients on renal replacement therapy and HIV-
infected patients. In children, all studies (n = 5) provided evi-
dence for 18F-FDG PET/CT to be a valuable tool for investi-
gation and management in children with FUO. The weighted
mean sensitivity, specificity, PPV, NPV, and clinical impact
were 84.7%, 67.7%, 82.4%, 76.6%, and 53.5%, respectively.
In the single study focusing on elderly, 18F-FDG PET/CT rep-
resented a diagnostic utility of 63%. Poor renal clearance of
18
F-FDG and immunosuppression may reduce contrast
between sites of lesions and background tracer activity, how-
ever the diagnostic values of 18F-FDG PET/CT in patients on
renal replacement therapy and HIV-infected patients seemed
not to be significantly different in these specific patient
groups compared to all FUO cases. In all reviewed sub-
groups, 18F-FDG PET/CT provide us an effective tool in the
diagnostic workflow for FUO.
It must be noted that critically ill patients were not
reviewed as a specific patient group because of their intrinsic
complex clinical conditions, making it often unclear if they
fulfil the criteria of FUO. However, a recent meta-analysis
performed by Huang et al. in critically ill patients with a sus-
pected infection showed a very high sensitivity of 94% and
an acceptable specificity of 66%.75
Although 67Ga-citrate scintigraphy is currently classified as
an older imaging technique, it still provides reasonable diag-
nostic values in the search for a final diagnosis in fever of
unknown origin. Weighted mean sensitivity, specificity, PPV,
NPV and helpfulness in diagnosis of FUO turned out to be
42.2%, 80.3%, 82.4%, 41.9%, and 42.2% respectively for
67
Ga-citrate scintigraphy. A comparison between 67Ga-citrate
scintigraphy and 18F-FDG PET/CT was made by two
research groups. In both studies, a superior sensitivity and
helpfulness for 18F-FDG PET/CT was observed. 67Ga-citrate
scintigraphy could, however, still be used in those centres
who have no access to a PET/CT camera system.
For WBC scintigraphy, the weighted mean sensitivity,
specificity, PPV, NPV, and accuracy were 73.5%, 86.3%,
79.1%, 82.4%, and 79.5%, respectively. WBC scintigraphy
could also be suitable for further investigation of FUO as an
alternative for 18F-FDG PET/CT. However, due to the charac-
teristics of WBC scintigraphy, it might be better to be
reserved for those patients with potential diagnostic clues for
an underlying infection, if possible, because malignancies
and noninfectious inflammatory diseases might be missed
with this technique.
Comparing 18F-FDG PET/CT with diagnostic CT, PET/CT
was necessary for diagnosis in 26% of all cases and has been
found superior with a higher sensitivity (89% for PET/CT vs
75% for CT). In general, a diagnostic CT scan is not neces-
sary to perform together with the 18F-FDG PET, since in
most cases a low dose CT is enough for adequate anatomical
Molecular Imaging of Fever of Unknown Origin: An Update
localization of the 18F-FDG uptake. In those cases, where the
exact location cannot be determined a specific contrast
enhanced CT scan of the part of the body where the 18F-
FDG is, can be performed. Based on the limited comparison
between 18F-FDG PET/CT and whole-body MRI in six
patients, MRI might be an important evolution in the investi-
gations for the cause of FUO. However, still no major studies
have been done and therefore it is unknown which of the
two modalities provides a better performance. Unluckily, no
studies were performed with 18F-FDG PET/MRI yet, there-
fore it is not known if a combined 18F-FDG PET/MRI investi-
gation will provide a significant better diagnostic value for
FUO patients or subgroups. Important for all patients, but
especially for children, one of the principal advantages of
using MRI instead of CT is a reduction of radiation exposure.
Although, with the advent of total body PET/CT systems, a
reduction in radiation exposure may also be envisioned.
Although an implementation of 18F-FDG PET/CT in the diag-
nostic workup of FUO is suggested in multiple
studies,1,13,34,76,77 18F-FDG PET/CT is, to our knowledge, only
structural included in the most recent guideline of the American
Academy of Family Physicians (AAFP; 2022) which suggest to
perform 18F-FDG PET/CT as an additional diagnostic test.78 To
consolidate 18F-FDG PET/CT in the diagnostic guidelines for
FUO, there is need for studies with homogeneous patient popu-
lations and clear referring conditions, investigating at which time
point in the diagnostic workup 18F-FDG PET/CT should be
implemented. These studies must not only focus on the diagnos-
tic value, but also on cost-effectiveness.
Conclusion
18
F-FDG PET/CT is the state-of-the-art, widely distributed and
accessible whole body nuclear imaging technique in the diag-
nostic management of fever of unknown origin at this
moment. The diagnostic value of this imaging technique has
been proven in many studies and even in children, elderly,
patients with end-stage renal disease or connective tissue dis-
eases and HIV-infected patients this technique has added
value. The clinical helpfulness of 18F-FDG PET/CT is high. If
18
F-FDG PET/CT is unavailable, the best alternative molecular
imaging techniques are 67Ga-citrate and WBC scintigraphy.
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