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\begin{document}

\title{The utility of PET/CT in diagnosing fever of unknown origin: The
experience of a large tertiary medical center}



\author[1]{Hussein Mahagna}%
\author[1]{Keren Vaknin}%
\author[2]{Abdulla Watad}%
\author[3]{Arsalan Abu-Much}%
\author[1]{Naim Mahroum}%
\author[1]{Ora Shovman}%
\author[4]{Jennifer Ben Shimol}%
\author[5]{Yehuda Shoenfeld}%
\author[3]{Howard Amital}%
\author[6]{Tima Davidson}%
\affil[1]{Sheba Medical Center}%
\affil[2]{Department of Medicine 'B', Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel, Sackler Faculty of Medicine, Tel-Aviv University, Israel }%
\affil[3]{Affiliation not available}%
\affil[4]{Edith Wolfson Medical Center}%
\affil[5]{Tel-Aviv University}%
\affil[6]{Sheba Medical Center at Tel Hashomer}%


\vspace{-1em}



  
  \date{May 23, 2024}


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\selectlanguage{english}
\begin{abstract}
Background: Fever of unknown origin (FUO) is a diagnostic challenge.
Positron emission tomography with computed tomography (PET/CT) is
expensive and not widely available. We aimed to evaluate the diagnostic
yield of PET/CT in the workup of FUO, and identify the patients for whom
this test is most useful. Methods: We reviewed the records of all
patients admitted to Sheba Medical Center from 2013 to 2017 who were
underwent PET/CT for the evaluation of FUO. Results: Of the 128 patients
included, PET/CT was helpful in revealing the cause of FUO in 61 (48\%).
A final diagnosis was made in 95 (74\%) patients. Of the 128 PET/CT
tests conducted for the workup of FUO, 61 (48\%) had true positive
results, 25 (20\%) false positive results, 24 (19\%) true negative
results, and 18 (14\%) false negative results. In a multivariate
analysis, helpfulness of PET/CT was independently associated with weight
loss and low hemoglobin. The calculated test sensitivity was 77\%,
specificity was 49\%, positive predictive value was 71\% and negative
predictive value was 57\%. Conclusion: PET/CT is valuable in the
diagnostic workup of FUO. When used as a complementary test, it was
helpful in diagnosing almost half the patients, and especially in those
with low hemoglobin and weight loss.%
\end{abstract}%



\sloppy




\textbf{What is already known about this topic?}

-PET/CT occupies a varying place within the work-up of fever or unknown
origin.

-While PET/CT is an expensive study, in institutions where this study is
performed, it often helps to uncover the source of fever of unknown
origin.

-PET/CT is most sensitive in uncovering malignant sources of fever.

\textbf{What does this article add?}

-PET/CT may uncover the source of fever in up to half of cases of fever
of unknown origin, where prior work-up was unrevealing.

-Infection was the most common source of fever identified by PET/CT.

-PET/CT was most useful in diagnosing the cause of fever in patients
with anemia and weight loss.

\textbf{Introduction}

Fever of unknown origin (FUO) is a frequently encountered condition on
internal medicine wards. It was first defined in 1961 as a fever greater
than 38.3\selectlanguage{ngerman}°C (101°F) for 3 weeks or more, whose origin is not identified
despite a thorough work-up {[}1{]}. The recommended work-up has been
modified over the years. While an abundance of studies may aid in the
diagnosis, FUO often poses a great challenge to clinicians, and nearly
half the patients ultimately do not receive a definitive diagnosis
{[}2-4{]}.

Positron emission tomography with computed tomography (PET/CT) combines
regular CT with nuclear imaging based on the enhanced uptake of
fluorodeoxyglucose (\textsuperscript{18}F-FDG) by highly metabolic
inflammatory and malignant cells. In the last decade, the PET/CT
modality has gained widespread popularity. Several prospective and
retrospective studies have suggested an important role of PET/CT in the
work-up of FUO {[}5-8{]}. Nonetheless, much heterogeneity remains
regarding the place of PET/CT within the algorithm of recommended
studies. Some consider PET/CT a mandatory part of the work-up, while
others regard it as a complementary test that may be performed following
the use of other imaging modalities such as CT scans. Differences in
study methodologies have produced variable results regarding the value
of PET.

Given the lack of widespread availability of PET/CT, and its high costs,
the population of FUO patients that is expected to gain benefit from
this modality needs to be further characterized. In the current study,
we assessed the utility of PET/CT in revealing the correct cause of FUO
and evaluated for parameters that may increase the likelihood of
diagnostic yield in patients with FUO.

\textbf{Methods}

\emph{Study design}

We reviewed the medical records of all the patients who underwent PET/CT
scans as part of FUO work-up between January 1, 2013 and January 30,
2018, at the Chaim Sheba Medical Center (Ramat Gan, Israel). With more
than 1,900 beds, this is the largest and most comprehensive tertiary
medical center in the Middle East.

Imaging data weas obtained from the picture archive and communication
system (PACS, Carestream Health 11.0, Rochester, NY) and clinical data
was obtained from the computerized medical records within our medical
center.

\emph{Participants}

The diagnosis of FUO was made according to the classic Petersdorf's
criteria, body temperature \textgreater{}38.3°C on several occasions for
at least 3 weeks with no diagnosis despite one week of inpatient or
outpatient work-up {[}1{]}. This work-up included a thorough history and
physical examination, a complete blood count, blood chemistry, blood
cultures, hepatitis serologies in the case of abnormal liver tests,
urinalysis, and a chest radiograph. In those patients who were admitted,
the workup also included more extensive inflammatory and infectious
serologies, and abdominal ultrasound or CT.

In our facility, PET/CT was not considered a standard part of the
initial workup for patients with FUO, and its usage was preserved for
those without a diagnosis despite a complete work-up. Study exclusion
criteria were age below 18 years, pregnancy, insufficient data from
medical records, active solid or hematologic malignancy, neutropenia,
nosocomial infections, or HIV carrying status.

\emph{FDG-PET/CT imaging technique}

FDG-PET/CT examinations were performed with a combined FDG-PET/CT
scanner (Philips Gemini GXL, Philips Medical Systems, Cleveland OH, USA)
that includes a 16-detector row helical CT. This enables simultaneous
acquisition of up to 45 trans axial PET images with inter-slice spacing
of 4 mm in one bed position; and provides an image from the vertex to
the thigh, with about 10 bed positions. The transaxial field of view and
pixel size of the PET images reconstructed for fusion were 57.6 cm and 4
mm, respectively, with a matrix size of 144x144. The technical
parameters used for CT imaging were pitch 0.8, gantry rotation speed 0.5
s/rotation, 120 kVp, 250 mAs, 3 mm slice thickness, and specific
breath-holding instructions {[}9-11{]}.

After 4-6 h of fasting, patients received an intravenous injection~of
370 MBq F-18 FDG. About 75 min later, CT images were obtained from the
vertex to the mid-thigh for about 32 s. When intravenous contrast
material was used, CT scans were obtained 60 s after injection of 2
mL/kg of non-ionic contrast material (Omnipaque 300; GE Healthcare). An
emission PET scan followed in 3D acquisition mode for the same
longitudinal coverage, 1.5 min per bed position. CT images were fused
with the PET data and were used to generate a map for attenuation
correction. PET images were reconstructed using a line of response
protocol with CT attenuation correction, and the reconstructed images
were generated for review on a computer workstation (Extended Brilliance
Workstation, Philips Medical Systems, Cleveland OH, US {[}9-11{]}.

\emph{Image assessment}

An experienced physician with two specializations (nuclear medicine and
radiology, TD), with 20 years' experience, reviewed all the cases
identified in the current study. FDG uptake in the lesions was measured
by standardized uptake values max (SUVmax), which was calculated by
manually generating a region of interest over the sites of abnormally
increased FDG activity {[}9-11{]}.

\emph{Data collection and review of PET/CT contribution}

For each patient, we collected data on their demographics, medical
history, current episode of fever, laboratory tests, and imaging
studies. We examined the PET/CT results and reviewed the final diagnosis
if it was made within 3 months of discharge. Finally, we evaluated the
results of the PET/CT studies and concluded whether the test was
contributory to the final diagnosis. This was determined by two internal
medicine consultants. When controversies arose regarding the
contributory value of a test, a third physician reviewed the data, and a
decision was made based on the rule of the majority.

Tests were considered true positives and therefore contributory if they
had positive findings that were relevant to the diagnosis. Studies were
labelled as true negative if no positive hypermetabolic findings were
observed, and no clinical diagnosis was established during 3 month
follow-up. True negative tests (negative PET/CT scan, with no diagnosis
made within 3 months) were not considered contributory since excluding
diagnoses were not considered of value. Tests were called false positive
if PET/CT showed hypermetabolic findings, but these findings did not add
to the final diagnosis; or if no diagnosis was made at all within 3
months of follow-up. They were considered false negative if no
hypermetabolic findings were observed and the diagnosis was made by
other means of investigations.

\emph{Statistical analysis}

Descriptive statistics were used to characterize the basic features of
the data in the study. We compared the features of patients who had
contributory tests to those who had non-contributory ones. We used the
Chi-square test and Fisher's exact test for categorical variables, and
the T-test and Mann Whitney U test for continuous variables, as
appropriate. A p-value of less than 0.05 was considered significant in
all the tests. Parameters found to be significantly associated with
contributory results of PET/CT (true positive) on univariate analysis
were analyzed in a multivariate analysis using forward step logistic
regression analysis.

\emph{Ethical approval}

This single-institution study was approved by the institutional review
board of Sheba Medical Center (SMC-18-4875). Informed consent was waived
by the institutional review board due to the retrospective nature of the
study. All methods were performed in accordance with the institution's
guidelines and regulations.

\textbf{Results}

\emph{Study population}In total, 225 patients were identified as having
undergone PET/CT scans as part of an FUO workup. Of them, 97 did not
meet study inclusion criteria (Fig. 1). Of the 128 patients who met
eligibility criteria and were included within the cohort, 80 (62.5\%)
were males. The mean age of the patients was 59 ± 20.3 years (range:
18-93). The mean duration of fever (prior to the performance of PET/CT)
was 38 days. Twenty-nine (22.8\%) of the patients were considered
immunosuppressed, due to concomitant treatment with corticosteroids (19
patients) or other immunosuppressive drugs, some of whom were also
receiving corticosteroids (19 patients), or by having medical conditions
that cause immunosuppression. Twenty-two (17\%) patients had implanted
prosthetic devices, including vascular implants, pacemakers and heart
valves. Table 1 presents the demographic and clinical characteristics of
the study population, according to whether PET/CT provided contributory
results.

\emph{Final diagnoses} By the completion of the work-up, 95 patients had
(74.2\%) received a final diagnosis. Most (64.2\% of the diagnosed
patients and 47.7\% of the study population) were diagnosed with
infectious diseases (Table 2). These included pulmonary infections
(n=12), endovascular infections (n=7), endocarditis (n=7), bacteremia
(n=4), and osteomyelitis (n=2). Twenty-one (16.4\%) of the patients were
diagnosed with inflammatory diseases, including arthritis (n=3), adult
onset Still's disease (n=3), and vasculitis (n=3). Malignancies were
diagnosed in 12 patients (9.4\%), nine (75\%) of which were hematologic,
and included lymphoma (n=6) and leukemia (n=3). One patient (0.8\%) was
diagnosed with Kikuchi disease. No compatible diagnosis was made for 33
(25.8\%) patients at 3 months following admission. The different
diagnoses are presented in Table 2. Figures 4-7 show PET/CT scan images
of four patients with FUO who were included in the study.

\emph{Contribution of PET/CT to FUO workup} Overall, 86 (67.2\%) of the
128 included patients had positive findings in PET/CT scans. In 61
(47.7\%) patients, the results were deemed true positive for leading to
the final diagnosis. The remaining 25 (19.5\%) had false positive
results (Fig. 2).

Forty-two (33\%) of the included patients did not have pathological FDG
uptake findings on PET/CT. Indeed, twenty-four (18.8\% of the study
population and 57.0\% of patients without diagnostic findings on PET/CT)
did not have a final diagnosis at the end of the workup or at 3 months
follow-up and were thus considered true negative. The remaining 18
(14\%) patients without a pathological FDG uptake on PET/CT were
eventually diagnosed using other modalities and were therefore
considered false negative (Fig. 2).

Findings yielded a sensitivity of 77.2\%, specificity of 49\%, positive
predictive value of 70.9\%, and negative predictive value of 57.1\%.

\emph{PET/CT contribution according to disease category} Of patients
with final diagnoses of inflammatory and infectious conditions, the
rates of true positive results were 60.0\% and 61.7\%, respectively and
the rates of false negative results were 30.0\% and 20.0\%,
respectively. Of the patients who were given a final diagnosis of
malignancy, 8.3\% of them had false positive results. None had false
negative results (Fig. 3).

\emph{Parameters associated with true positive results}In a univariate
analysis, weight loss, low concentrations of hemoglobin and low levels
of transferrin were associated with true positive diagnoses (Table 1).
In a multivariate analysis, hemoglobin was inversely associated with
contributory PET/CT tests (odds ratio (OR): 0.597, 95\% confidence
interval (CI) 0.412-0.866, p=0.006). Weight loss, on the other hand, was
positively associated with contributory PET/CT tests (OR: 3.605, 95\% CI
1.123-11.576, p=0.031). The association of low-level transferrin with a
diagnostic PET/CT was not significant: (OR: 0.992, 95\% CI 0.981-1.003,
p= 0.13) (Table 3).

\textbf{Discussion}

In this retrospective study, PET/CT proved helpful in diagnosing almost
half of all patients who underwent scans as part of FUO work-up. The
management of patients with FUO has evolved considerably since this
entity was initially described. Nevertheless, many patients remain
undiagnosed despite extensive testing. Review of the current literature
suggests that PET/CT is a useful part of work-up though reports vary
widely, citing numbers which range from 42\% to 72\% of cases in which
they assisted in the diagnosis {[}5-8,12-21{]}. The variability of
results reported can be explained, in part, by differences in the
methodologies employed, definition of FUO, the varying work-up
algorithms and the fluctuating place of PET/CT within the algorithms,
technique and model of the PET scanners, and how different groups define
whether PET/CT is helpful to establishing the diagnosis. This diversity
makes it difficult to compare among the published studies.

In a prospective study by Schönau et al. {[}8{]}, PET/CT scan was a
mandatory part of the work-up of FUO. All patients with FUO who
presented to internal medicine wards were included. PET/CT yielded true
positive results in 56.7\% of the patients with FUO. In contrast, we
included only patients without a diagnosis after a thorough medical
workup; 44.0\% of them underwent CT-scans before advancing to a PET/CT
scan.

Our rate of false negative results of PET/CT scans, 14.1\%, is
comparable to rates reported in the literature. Two thirds of these
patients were diagnosed with infectious diseases and one third with
inflammatory diseases (familial Mediterranean fever, adult-onset Still's
disease, polymyalgia rheumatica and temporal arteritis) while none were
diagnosed with malignant diseases. Schönau et al. {[}8{]} found false
negatives in only 5\% of their cohort. In an early study, Gafter-Gvili
et al. {[}7{]} reported a rate of false negatives of 18\%; of them, 40\%
were eventually diagnosed with infectious diseases, and one patient with
a malignant disease. This patient was subsequently diagnosed with
marginal zone lymphoma based on bone marrow biopsy.

False positive results were found in one fifth of our patients. One
patient was diagnosed with lymphoma, eleven were found to have
infections, and 2 were diagnosed with inflammatory conditions. In the
remaining 44\%, no diagnosis was made at the end of the work-up or at 3
month follow-up. Non-specific findings and physiologic uptake were not
considered positive results. Our false positive rates match those
reported by other studies which range between 9\% and 30\%
{[}3,7,22,23{]}.

Similar to other studies, infectious diseases were the most common cause
for FUO in close to half of patients, followed by inflammatory diseases
which were identified in 16.4\% {[}1,2,7,24{]}. PET/CT was helpful in
diagnosing just over 60\% of the infectious cases while it guided
clinicians toward the correct diagnosis in exactly 60\% of those with
inflammatory diseases. Malignant causes of FUO mostly included
hematologic malignancies which made up almost three quarters of these
cases. For more than 90\% of patients with malignant causes of FUO, the
PET/CT test provided true positive results. PET/CT appears to have
missed the diagnosis of cancer in only one patient, whose scan showed
increase uptake in the lungs and was ultimately diagnosed with T-cell
lymphoma through other diagnostic modalities. Accordingly, PET/CT
demonstrated highest efficiency in diagnosing malignant causes of FUO.

In our study, weight loss and low hemoglobin levels were independently
associated with PET/CT producing true positive results in yielding the
cause of FUO. Likewise, Crouzet et al. {[}5{]} illustrated an
association between low hemoglobin levels and true positive PET/CT
scans. In addition, other studies have shown similar associations
between true positives and the presence of adenopathy and elevated
levels of c-reactive protein (CRP) {[}5,6,8{]}. We, however, did not
find a significant association between true positive results and
biomarkers of inflammation such as leukocytosis and elevated CRP.
Finally, in the study published by Gafter-Gvili {[}7{]}, in which PET/CT
was defined as helpful if it led either to true positives or true
negatives, both fever and male gender were significant predictors of
PET/CT usefulness.

A key limitation of this study is its retrospective design. As a result,
the diagnosis and workup of FUO were not standardized before proceeding
to PET/CT. Nevertheless, our study produced reliable data on the
usefulness of PET/CT in the work-up of FUO. We collected a large group
of patients while excluding all those that did not meet acceptable
criteria. We adhered to strict methodology in how we defined useful
PET/CT scans and discounted all PET/CT findings which were not
diagnostic. With our standardized protocol, we identified in which
patients PET/CT may be most valuable in assisting in the diagnosis of
FUO.

\textbf{Conclusion}

In our study, PET/CT test was found to be highly beneficial in the
work-up of FUO. It led to the diagnosis in nearly half of the patients
in which a diagnosis could not be established following a thorough
medical evaluation. Moreover, in patients with weight loss and anemia,
PET/CT is most likely to be helpful in reaching the final diagnosis.
Clinicians should be aware of the clinical utility of PET/CT and its
place in the work-up of FUO following the completion of routine testing.

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\textbf{Conflict of interest Statement}

No specific funding was received from any bodies in the public,
commercial or not-for-profit sectors to carry out the work described in
this article.

\textbf{The authors whose names are listed immediately below declare
that there is no conflict of interest.} They certify that they have NO
affiliations with or involvement in any organization or entity with any
financial interest (such as honoraria; educational grants; participation
in speakers' bureaus; membership, employment, consultancies, stock
ownership, or other equity interest; and expert testimony or
patent-licensing arrangements), or non-financial interest (such as
personal or professional relationships, affiliations, knowledge or
beliefs) in the subject matter or materials discussed in this
manuscript.

\textbf{Authors:} Hussein Mahajna, Keren Vaknin, Abdulla Watad, Arsalan
Abu-Much, Naim Mahroum, Ora Shovman, Jennifer Ben Shimol, Yehuda
Shoenfeld, Howard Amital, Tima Davidson

\textbf{Hosted file}

\verb`The utility of PET FUO Figures.docx`  available at \url{https://authorea.com/users/353518/articles/477354-the-utility-of-pet-ct-in-diagnosing-fever-of-unknown-origin-the-experience-of-a-large-tertiary-medical-center}

\textbf{Hosted file}

\verb`The utility of PET FUO Tables.docx`  available at \url{https://authorea.com/users/353518/articles/477354-the-utility-of-pet-ct-in-diagnosing-fever-of-unknown-origin-the-experience-of-a-large-tertiary-medical-center}

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