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ORIGINAL ARTICLE
18
F-FDG PET/CT in inflammation of unknown origin:
a cost-effectiveness pilot-study
H. Balink &S. S. Tan &N. J. G. M. Veeger &F. Holleman &
B. L. F. van Eck-Smit &R. J. Bennink &H. J. Verberne
Received: 25 August 2014 / Accepted: 5 January 2015
#Springer-Verlag Berlin Heidelberg 2015
Abstract
Purpose Patients with increased inflammatory parameters,
nonspecific signs and symptoms without fever and without a
diagnosis after a variety of diagnostic procedures are a diag-
nostic dilemma and are referred to as having inflammation of
unknown origin (IUO). The objective of this pilot study was to
compare the cost-effectiveness of a diagnostic work-up/strat-
egy with and without
18
F-FDG PET/CT in patients with IUO
using a published dataset as a reference.
Methods IUO patients without
18
F-FDG PET/CT (group A,
46 patients) and IUO patients referred for
18
F-FDG PET/CT
(group B, 46 patients) were selected. IUO was defined as the
combination of nonspecific signs and symptoms and a
prolonged erythrocyte sedimentation rate (ESR), defined as
≥age/2 in men and ≥(age+ 10)/2 in women (ESR in
millimetres per hour and age in years), and/or C-reactive pro-
tein (CRP) ≥15 mg/l. The costs of all tests and procedures and
the number of hospitalization days in each patient to reach a
diagnosis were calculated using current Dutch tariffs.
Results In group A a diagnosis was reached in 14 of the 46
patients. The mean cost per patient of all the diagnostic pro-
cedures was €2,051, and including the cost of hospitalization
was €12,614. In group B a diagnosis was reached in 32 of the
46 patients. The mean cost per patient of all the diagnostic
procedures was €1,821, significantly lower than in group
A(p<0.0002), and including the cost of hospitalization was
€5,298.
Conclusion In IUO
18
F-FDG PET/CT has the potential to
become a cost-effective routine imaging technique indicating
the direction for further diagnostic decisions thereby allowing
unnecessary, invasive and expensive diagnostic investigations
to be avoided and possibly the duration of hospitalization to be
reduced. However, a prospective multicentre “bottom-up
microcosting”cost-effectiveness study is warranted before
these preliminary data can be extrapolated to clinical practice.
Keywords
18
F-FDG PET/CT .Unexplained inflammatory
syndrome .Inflammation of unknown origin (IUO) .
Cost-effectiveness
Introduction
Inflammation of unknown origin (IUO) is defined by an in-
creased C-reactive protein (CRP) level or erythrocyte sedi-
mentation rate (ESR) in patients presenting with nonspecific
signs and symptoms including fatigue, malaise, weight loss,
anorexia, subfebrile temperatures or night sweats and without
a diagnosis after conventional diagnostic procedures. Just as
in fever of unknown origin (FUO), the aetiology of IUO may
vary from a self-limiting condition to occult malignancy [1,
2]. The literature on IUO is scarce and does not yet allow a
uniform diagnostic strategy. In the search for the origin of
IUO, patients may undergo extensive and expensive
H. Balink (*)
Department of Nuclear Medicine, Medical Center Leeuwarden,
P.O. Box 850, 8901 BR Leeuwarden, The Netherlands
e-mail: hans.balink@znb.nl
S. S. Tan
Erasmus University Rotterdam, Institute for Medical Technology
Assessment, Rotterdam, The Netherlands
N. J. G. M. Veeger
Department of Epidemiology, University Medical Center Groningen,
Groningen, The Netherlands
F. Ho l lem a n
Department of Internal Medicine, Academic Medical Center
Amsterdam, Amsterdam, The Netherlands
B. L. F. van Eck-Smit :R. J. Bennink :H. J. Verberne
Department of Nuclear Medicine, Academic Medical Center,
Amsterdam, The Netherlands
Eur J Nucl Med Mol Imaging
DOI 10.1007/s00259-015-3010-0
investigations that may not only be inappropriate but also
expose patients to the risks of these investigational proce-
dures, e.g. lumbar or bone marrow biopsy and gastroduodenal
or colonic endoscopy.
The nonspecificity of
18
F-FDG and the synergy of integrat-
ing functional and anatomical images with hybrid PET/CT
may offer substantial benefit in the diagnostic work-up of
patients with IUO. Furthermore, metabolic PET imaging with
18
F-FDG is able to reveal functional alterations that precede
morphological changes [3]. Four recent studies have shown
that the diagnostic yield, the character of the underlying aeti-
ologies, i.e. infection, noninfectious inflammatory diseases
(NIID) and malignancy, and the diagnostic contribution of
hybrid
18
F-FDG PET/CT are quite similar in patients with
IUO and FUO [4–7].
18
F-FDG PET/CT showed a high nega-
tive predictive value for focal diseases and based on
18
F-FDG
PET/CT a cause could be correctly identified or excluded in
approximately 90 % of patients.
18
F-FDG PET/CT has the
potential to speed up the diagnostic process and may allow
further unnecessary, invasive and expensive diagnostic tests or
inappropriate therapeutic trials with steroids or antibiotics to
be avoided [5,8]. Despite the Dutch tariff of €1,148, the in-
clusion of
18
F-FDG PET/CT could therefore be cost-effective.
However no data on cost-effectiveness of
18
F-FDG PET/CT in
this population are available.
To assess whether there would be value in a prospective
multicentre study, the objective of this pilot study was to com-
pare the cost-effectiveness of a diagnostic work-up/strategy
with and without
18
F-FDG PET/CT in patients with IUO using
a published dataset as a reference [9]. In addition, the extent to
which the introduction of
18
F-FDG PET/CT changed the di-
agnostic work-up of patients with IUO could be estimated.
Materials and methods
Patient selection
Group A To reflect a quite recent clinical situation without the
use
18
F-FDG PET/CT, the dataset from a retrospective study
by Perrin et al. [9] was used. In this study 46 patients were
retrieved from the medical files of Strasbourg University
Hospital (France) for the period from April 1992 to
June 1999. Inclusion criteria were prolonged ESR, de-
fined as ≥age/2 in men and ≥(age+10)/2 in women
(ESR in millimetres per hour and age in years), and/or
CRP ≥15 mg/l, and nonspecific signs and symptoms.
Exclusion criteria were: (sub)febrile temperature without
increased inflammatory parameters, regression of the inflam-
matory syndrome during evaluation, incomplete medical files,
and patient refusing further investigations after initial diagnos-
tic work-up [9].
Group B This group consisted of IUO patients referred for
18
F-FDG PET/CT. To ensure adequate comparability between
the two patient groups (group A and group B) the same inclu-
sion and exclusion criteria of Perrin et al. [9] were used. Data
on 46 age-matched and gender-matched patients with IUO
who were referred for
18
F-FDG PET/CT were extracted from
the digital hospital information system of the Medical Center
Leeuwarden. Querying of the databases was limited to the
period from January 2013 to November 2013.
Methodology of cost analysis
In this retrospective analysis the cost-effectiveness of
18
F-
FDG PET/CT in patients with IUO was estimated from a
‘hospital perspective’, in the setting of a relatively large teach-
ing hospital. Indirect cost components from a ‘healthcare pro-
viders perspective’that concerned overheads (e.g. general ex-
penses, administration, energy, maintenance, personnel costs)
were not included in the analysis. Medication costs were ex-
plicitly excluded from this study, because the medications
used are considered to be highly dependent on the disease
and treatment strategy under consideration and often explain
total cost differences between alternative treatments in eco-
nomic evaluations.
Direct cost components were all the diagnostic tests and
procedures, and the number of hospitalization days, in each
patient to reach a diagnosis. For group A the dataset of diag-
nostic procedures without the use of
18
F-FDG PET/CT and the
number of hospitalization days were used as described by
Perrin et al. [9], whose study is to the best of our knowledge
the only one that describes all diagnostic procedures and hos-
pitalization days needed for the evaluation of patients with
IUO without the use of either
18
F-FDG PET or
18
F-FDG
PET/CT.
To prevent a potential bias resulting from different costing
methodologies, the theoretical costs were not calculated using
the unit costs of diagnostic procedures of the two hospitals.
Instead, the tariffs of the Dutch Healthcare Authority were
used (Nederlandse Zorgauthoriteit, NZa; http://www.nza.nl/
regelgeving/tarieven/, TB/CU-7078-01 of 1 January 2014),
together with the reference prices of the most recent update
of the Dutch Manual for Costing in Economic Evaluations
[10]. Costs were based on 2014 cost data and when
necessary costs were adjusted to 2014 using the general
price index from the Dutch Central Bureau of Statistics
(http://statline.cbs.nl). Total directs costs of the two
diagnostic strategies (with and without
18
F-FDG PET/CT)
were determined by multiplying the total number of each
diagnostic procedure by the corresponding current Dutch
tariff.
Concerning laboratory analyses for both groups the current
tariff of €56 for a total blood examination (haematology,
chemistry) and urinalysis was applied to both groups. As for
Eur J Nucl Med Mol Imaging
group A, no specific tariff was applied for standard radiogra-
phy, CT, US and MRI investigations (e.g. thoracic or abdom-
inal) the mean current tariff was used. The mean current tariff
was also used for endoscopy (bronchial, gastroduodenal or
colonic). Additional costs in group B due to diagnostic proce-
dures resulting from false-positive
18
F-FDG PET/CT results
were included in the analysis.
SAS version 9.2 (SAS Institute Inc., Cary, NC) was used
for statistical analyses.
18
F-FDG PET/CT
The time point for requesting the
18
F-FDG PET/CT scan was
chosen by the referring physician. The imaging protocol, in-
terpretation and analysis of hybrid PET/CT images have pre-
viously been described in detail [6,11].
Follow-up and f inal diagnosis
The final diagnoses were not based on the
18
F-FDG PET/CT
results alone; only sufficiently validated diagnoses were used.
Information concerning final diagnoses and methodology was
derived from the hospital information system. This included
both invasive and non-invasive procedures, such as biopsy
and surgery, serology or cultures (blood, urine or tissues) or
a clear response to therapy. Follow-up was obtained in all
patients. Only diagnoses obtained within 4 months of the
18
F-FDG-PET/CT scan were considered to be related to the
PET/CT result.
According to Dutch legislation, retrospective data collec-
tion does not require approval of an ethics committee. All
procedures were performed as part of clinical care, and the
data were anonymized for the current analysis.
Results
Patient characteristics
For group A, 376 files were initially extracted from the hos-
pital information system in Strasbourg, and 46 patients were
considered eligible. For group B, from among the 1,880
18
F-FDG PET/CT scans performed in Leeuwarden be-
tween January 2013 and November 2013, 385 were per-
formed for non-oncological reasons and were considered
potentially eligible. The hospital information system was
searched backwards in time stopping after 46 eligible
patients (using the same inclusion and exclusion criteria
described by Perrin et al. [9]) had been found. Patient
characteristics are listed in Table 1.
18
F-FDG PET/CT effectiveness
Group A Without
18
F-FDG PET/CT a diagnosis was reached
in 14 of the 46 patients (infection in 2 patients, NIID in 12
patients). In 13 patients the inflammatory syndrome resolved
spontaneously, and in 12 patients the inflammatory syndrome
persisted. Seven patients were lost to follow-up. No patients
died during 12 months of follow-up.
Group B With
18
F-FDG PET/CT a diagnosis was reached in
32 of the 46 patients (infection in 6 patients, NIID in 23 pa-
tients, malignancy in 3 patients). In 14 patients a diagnosis
was not reached during follow-up, The inflammatory syn-
drome subsided in 11 patients and persisted in 3 (obese) pa-
tients. Of the patients with a diagnosis, two died during
6monthsoffollow-up.
Number of diagnostic procedures and costs
The results are summarized in Table 2. In the patient group
without
18
F-FDG PET/CT higher numbers of imaging proce-
dures overall, and invasive and noninvasive diagnostic proce-
dures were performed.
Group A The estimated mean cost per patient of all diagnostic
procedures without
18
F-FDG PET/CT was €2,051. Adding the
cost of the mean number of 21 hospitalization days per patient
increased the mean cost to €12,614 per patient.
Group B The estimated mean cost per patient of all diagnostic
procedures with
18
F-FDG PET/CT was €1,821. Adding the
cost of the mean number of 6.9 hospitalization days per patient
(median 1.5 days, range 0 –32 days) increased the mean cost
to €5,298 per patient.
The cost per patient in group B excluding the cost of
18
F-
FDG PET/CT (mean €673, range €90 –1,856) was signifi-
cantly lower than the mean cost per patient in group A.
Adding
18
F-FDG PET/CT to the diagnostic process in group
B increased the mean cost per patient to €1,821 (range €1,
238 –3,004), but this cost remained significantly lower than
the mean cost per patient in group A. The total cost in group B
included €1,120 from diagnostic procedures that followed five
Tabl e 1 Patient characteristics
Group A Group B
Male/female 15/31 17/29
Age (years), range (mean) 21 –90 19 –83 (64)
CRP (mg/l), range (mean) 10 –277 (73) 12 –268 (78)
ESR (mm/h), range (mean) 28 –140 (85) 25 –>100 (78)
a
Hospitalization days, range (mean) 5 –47 (21) 0 –32 (7)
a
Not available in 21 patients
Eur J Nucl Med Mol Imaging
false-positive
18
F-FDG PET/CT scans. In four patients with a
positive
18
F-FDG PET/CT-guided diagnosis, collateral false-
positive
18
F-FDG PET/CT results led to negative diagnostic
procedures (colonoscopy, gastroscopy, thyroid biopsy and ul-
trasonography of the breast in one patient each). In one patient
without a diagnosis, sigmoidoscopy guided by
18
F-FDG PET/
CT was without result.
Discussion
The use of
18
F-FDG PET/CT in the diagnostic work-up of
IUO in our hospital appears not to increase costs. Despite
the tariff of €1,148, the inclusion of
18
F-FDG PET/CT seems
to be cost-effective due to the decreased number of both inva-
sive and noninvasive procedures. Given the limitations of the
retrospective character of this study, the total cost in group B
(with
18
F-FDG PET/CT) seemed at least not higher than in
group A (without
18
F-FDG PET/CT). From a descriptive
point of view the cost in group B (with
18
F-FDG PET/CT)
was deemed lower.
Since the introduction of the PET/CT system in 2005 in our
hospital the referring physicians appeared to go through a
learning curve. This is expressed, for example, in the absence
of tumour marker determinations in group B. Referring phy-
sicians understand that abnormal
18
F-FDG PET/CT results not
only guide the bestbiopsy location but also provide an optimal
staging. This is reflected not only in the relatively low number
of biopsy and endoscopy procedures in group B, but also in
the observation that 6 of the total of 15 biopsies were per-
formed after the
18
F-FDG PET/CT scan. In group B, tests with
low costs and high accessibility were done before the
18
F-
FDG PET/CT investigation, and the larger proportion
(55 %) of the more expensive and/or invasive procedures
(e.g. endoscopy and biopsy) were performed after the
18
F-
FDG PET/CT investigation.
The role of ‘blind’biopsies in IUO or FUO is a matter of
discussion. This is illustrated by the finding of Hot et al. [12]
that the diagnostic yield of a ‘blind’bone marrow biopsy in
FUO is modest, even after careful patient selection. The yield
of bone marrow biopsy in 130 of 280 patients with FUO after
a routine diagnostic work-up was 23 % [12]. The con-
cept that
18
F-FDG PET imaging is able to reveal func-
tional alterations that precede morphological changes is
supported by the observation that in 19 of 23 patients
with a diagnosis of NIID, large-vessel vasculitis and/or
polymyalgia rheumatica was diagnosed and treated. This
raises the question as to what the
18
F-FDG PET/CT
resultswouldhavebeeninthe12patientsingroupA
with an unexplained persisting inflammatory syndrome.
In group B the inflammatory syndrome subsided in 11
patients, and in these patients with a self-limiting con-
dition there was apparently a beneficial and controlled
inflammatory or immune response [2]. In three (obese)
patients the question remains open as to whether this
reflects a state of low-grade systemic inflammation
Tabl e 2 Number of diagnostic procedures and costs
Procedure Cost per procedure (€) Group A (without
18
F-FDG PET/CT) Group B (with
18
F-FDG PET/CT)
No. of procedures Cost (€) No. of procedures Cost (€)
Laboratory (complete blood count,
routine blood chemistry, urinalysis)
56 46 2,576 46 2,576
Bacterial cultures 34 115 3,910 36 1,224
Tuberculin tests 25 42 1,050 3 75
Viral serology tests 93 46 4,278 14 1,302
Immunological tests 258 46 11,868 25 6,450
Tumour marker tests 30 78 2,340 0 0
Standard radiography 42 112 4,704 52 2,340
Ultrasound investigations 101 99 9,999 36 3,636
CT scans 187 39 7,293 13 2,431
MRI 272 0 0 4 1,088
Endoscopy 275 52 14,300 17 4,675
Biopsy (and histology) 195 75 14,625 16 3,120
Laparotomies 7,000 2 14,000 0 0
Interdisciplinary consultations 54 63 3,402 38 2,052
18
F-FDG PET/CT 1,148 0 0 46 52,808
Hospitalization days 457 966 441,462 318 145,326
Total 1,781 535,807 664 229,103
Eur J Nucl Med Mol Imaging
[13]. Adipose tissue is an active endocrine organ that
releases a variety of hormones and cytokines, such as
interleukin-6, that contribute to CRP elevation [14].
Literature on IUO and the role of
18
F-FDG PET/CT in IUO
is scarce compared to that on FUO. A PubMed literature
search for “
18
F-FDG”,“PET”,“PET/CT”,“inflammation”,
“unknown origin”,“unexplained”,“inflammatory”,“inflam-
mation”,“elevated CRP”and “ESR”resulted in only four
studies [1,5–7]. A PubMed literature search for “
18
F-FDG
PET/CT”,“FUO”and “febris eci”yielded 76 results, of which
more than 30 were reviews or meta-analyses. Only one pub-
lication dedicated to cost-effectiveness could be found: a
Spanish study that included 20 patients with FUO. The mean
cost per patient of the diagnostic procedures preceding the
18
F-FDG PET/CT scan was €11,167, including an average
of 11 days of hospitalization and outpatient controls [15]. This
cost is in line with our retrospectively calculated costs using
the data of Perrin et al. [9]. In addition the authors calculated
that if
18
F-FDG PET/CT had been performed earlier in the
diagnostic process (before endoscopy and other invasive pro-
cedures), €5,471 per patient would have been saved on diag-
nostic tests and hospitalization days.
Defining the cost-effectiveness of
18
F-FDG PET/CT in the
diagnosis of IUO and FUO is a relevant issue. The major
problem for cost-effectiveness calculations is the variety in
number and heterogeneity of the diagnostic procedures need-
ed prior to the patient fulfilling the criteria for either IUO or
FUO. After the investment in the considerable extra cost of
18
F-FDG PET/CT, in many patients further invasive or non-
invasive diagnostic procedures with high specificity are need-
ed to confirm or establish a diagnosis. Consequently, the cost
of
18
F-FDG PET/CT may be further increased by the risk of
false-positive results related to the high sensitivity and the
nonspecificity of the tracer, and the subsequent unnecessary
diagnostic procedures. The extra cost of €1,120 was 13 % of
the total cost of all diagnostic procedures in group B.
In the context of the heterogeneity of the IUO and FUO
patient populations, a distinction can be made between the
very detailed “microcosting”and the less precise “gross cost-
ing”methods [16]. Depending on their relevance for the cost-
benefit evaluation, the diagnostic procedures may be mea-
sured either for individual patients (“bottom-up approach”)
or for average patients (“top-down approach”)[17]. Further-
more, the evaluation of the diagnostic procedures may be
based on existing unit costs (e.g. reference prices) or on local
unit cost calculations. “Bottom-up microcosting”with the ap-
plication of a standardized costing methodology may enable
the most meaningful comparison of actual cost differences
between healthcare services, and allows the best identification
of costs directly used for a patient and insight into patient
subgroups. However, this methodology is lengthy and expen-
sive and has not been widely used in economic healthcare
evaluations [18]. Furthermore, the question is raised as to
whether the heterogeneity of the patients and the broad range
in possible diagnostic procedures will not undermine the ac-
curacy of “bottom-up microcosting”.
This comparative cost analysis has some limitations. The
study by Perrin et al. [9] had no intention to define or calculate
the cost-efficacy of the diagnostic procedures used. The main
goal was to describe the long-term follow-up and prognosis in
patients who were hospitalized (many on multiple occasions)
for an inflammatory syndrome without a causal diagnosis.
One may assume that the longer duration of hospitalization
was needed to perform all the necessary diagnostic proce-
dures. Evaluation on an outpatient basis was apparently lim-
ited and most likely a reflection of clinical practice of that era.
Current clinical practice shows an ongoing trend for a de-
crease in the number of hospitalization days. This is illustrated
for The Netherlands by the fact that the mean number of hos-
pitalization days per patient was 6.3 in 2005 and 4.8 in 2012
(http://www.nvz-ziekenhuizen.nl/_library/11481). In the
study by Perrin et al. [9] patients were selected and recruited
by internal medicine physicians. In our study the same
inclusion and exclusion criteria were used, but applied only
to those patients who were referred for
18
F-FDG PET/CT.
This difference may have caused a bias in patient selection.
Both patient populations were selected from different time
periods. Since the last patient of group A was included in
1999, healthcare has incorporated ongoing progression and
innovations in medical technology, e.g. laparotomy is more
expensive primarily because it requires more hospitalization
days than minimal invasive laparoscopic procedures used
nowadays [19]. Although we corrected for the change in
prices for procedures, it cannot be ruled out that in the two
cohorts there were differences in diagnostic work-up beyond
the FDG PET/CT era (i.e. 1989 –1992 vs. 2013). The fact that
indirect cost components as well as medication were excluded
represents a further limitation of the analysis. The timing of
18
F-FDG PET/CT may have caused a bias resulting in a more
favourable outcome for
18
F-FDG PET/CT: i.e. a
18
F-FDG
PET/CT scan performed earlier in the process may have lim-
ited additional investigations.
The limitations of this retrospective study suggest that
some restraint should be applied in the interpretation of the
results. In our opinion the results of this pilot study warrant a
prospective multicentre “bottom-up microcosting”cost-
effectiveness study of
18
F-FDG PET/CT in patients with
IUO. There would be some difficulty in developing a stan-
dardized protocol. The initial diagnostic procedures will con-
tinue to be based on the cues presented by a full physical
examination, and a thorough interview –including family
history, intoxication clues and travel history –with particular
attention toexposure to animals, work environment and recent
contact with persons exhibiting similar symptoms. Inevitably,
invasive procedures will be performed directed by localizing
complaints or cues [20]. Patients should be referred for
18
F-
Eur J Nucl Med Mol Imaging
FDG PET/CT based on a uniform definition of an appropriate
minimal diagnostic work-up. This work-up should contain at
least the following routine diagnostic procedures: extensive
blood and urine investigation, including ANA/ANCA, bacte-
rial cultures, and HIV, EBV and CMV tests, plus extra serol-
ogy based on local epidemiology, a tuberculin skin test, ECG,
chest radiography and abdominal ultrasonography. In addi-
tion, patients should be included before invasive diagnostic
procedures such as lymph node, liver, bone marrow or tem-
poral artery biopsy, endoscopies (of stomach, colon, bronchial
with their respective biopsies) and trans-oesophageal
ultrasonography.
Conclusion
In patients with IUO
18
F-FDG PET/CT has the potential to
become a cost-effective routine imaging technique indicating
the direction for further diagnostic decisions thereby allowing
unnecessary, invasive and expensive diagnostic investigations
to be avoided. In addition, these advantages could therefore
reduce the duration of hospitalization.
Conflicts of interest None.
Sources of funding None.
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