Positron emission tomography (PET) is a non-invasive diagnostic imaging
procedure utilized to assess the level of metabolic activity and perfusion of
the organ systems. The positron camera (tomograph) produces cross-sectional
tomographic images which are obtained from intravenously administered positron
emitting radioactive tracer substances (radiopharmaceuticals) such as 2-[F-18]
fluoro-d-glucose (FDG).

The noncoverage NCD for PET scan used for inflammation and infection
(220.6.16) retired effective January 1st 2021.1 This NCD address the use of
PET scan for non-oncological indications specific to inflammatory or
infectious etiologies including fever of unknown origin, several cardiac
conditions, osteomyelitis and infected artificial joints.

**Definitions**

First-line therapy is an agent used in the initial treatment of a condition.

An adverse event is a documented event that contraindicates further use of the
medication or side effects that are not likely to be transient and resolve
with further treatment or impair functional capacity and/or daily living
activities.

Lack of efficacy is the lack of an expected or desired effect related to
therapy when the dosage and duration of therapy meet published standards.

Refractory disease is when the patient fails to respond to all first-line
therapies that are standard of care for the condition.

Relapse disease is a recurrence of the disease condition that does not respond
to first-line treatments and/or standard of care therapies.

Fever of unknown origin defined as fever higher than 38.3 Celsius (101 degrees
Fahrenheit) on several occasions, duration of at least three weeks and
uncertain diagnosis after evaluation.2

Fever- temperature of 101 degrees Fahrenheit or 38.3 Celsius

Immunocompromised (defined as neutropenia for at least one week in the three
months before the start of the fever, known HIV infection,
hypogammaglobulinemia or use of 10 milligrams Prednisone or equivalent for at
least two weeks in the three months before the start of the fever)3



**Coverage**

**A. Fever of Unknown Origin (FUO)**

****

PET Scan will be considered reasonable and medically necessary for FUO when
all of the following conditions are met:

****

  1. **** Fever higher than 38.3 Celsius (101 degrees Fahrenheit)2,4 **AND**
  2. Present for  21 days defined by fever on  2 occasions with repeating episodes for  2 weeks prior to study 4,5 **AND**
  3. The patient is not immunocompromised3,4 **AND**
  4. Investigation including history, physical, laboratory analysis and standard imaging is non-diagnostic6 **AND**
  5. Patient does not have any conditions that would limit the ability to interpret the PET scan 7

**B. Cardiac**

**** PET scan for evaluation of cardiac sources of infection and inflammation
is considered reasonable and medically necessary when:

  1. Clinical exam and laboratory evaluation lead to clinical suspicion of the condition and this is documented in the medical record **AND**
  2. **** Non-specific or inconclusive imaging from echocardiography and/or CT6 **AND**
  3. PET scan is conducted with cardiac preparation protocol8,9 **AND**
  4. Patient does not have any conditions that would limit the ability to interpret the PET scan including **** cardiac/vascular surgery within the past 3 months10 **AND**
  5. The patient is being evaluated for one of the following conditions and the specific criteria has been met: 
    1. Infective Endocarditis: the patient has a prosthetic valve
    2. Cardiac Sarcoidosis:

      1. The patient has risk factor cardiac sarcoidosis (such as systemic sarcoidosis with cardiac findings, a young patient (<60) with unexplained, new onset conduction system disease, heart failure without explanation)11 **OR**

      2. For guiding subsequent treatment of proven cardiac sarcoidosis if PET scan is the primary test used (not in conjunction with cardiac MRI, CT or other nuclear imaging studies).
    3. Infection of cardiovascular implantable electronic devices:

      1. Patient is unable to undergo an MRI because of their device
      2. Diagnosis is inconclusive on standard imaging (echo/CT)
      3. Additional diagnostic studies would impact clinical care (such as decision to remove device)



    4. Vascular graft infection

      1. Diagnosis is inconclusive with CTA or MRA
      2. No conditions that would make PET scan study less diagnosis (such as surgical adhesives/recent surgery)
      3. Additional diagnostic studies would impact clinical care

Limitations:

1\. The need for PET scan and labeled WBC scan as part of diagnostic
evaluation is rare. Individual consideration may be given on redetermination
(appeal) for payment in rare, unique circumstances if the medical necessity of
both studies and clearly documented in the medical record. Frequent reporting
of these services together may trigger focused medical review.

2\. The need for PET scan and 67Ga SPECT/CT as part of diagnostic evaluation
is rare. Individual consideration may be given on redetermination (appeal) for
payment in rare, unique circumstances if the medical necessity of both studies
and clearly documented in the medical record. Frequent reporting of these
services together may trigger focused medical review.

3\. The need for PET scan and cardiac MRI as part of diagnostic evaluation is
rare. Individual consideration may be given on redetermination (appeal) for
payment in rare, unique circumstances if the medical necessity of both studies
and clearly documented in the medical record. Frequent reporting of these
services together may trigger focused medical review.

4\. Endocarditis- PET scan is not reasonable and necessary for use in native
value.

5\. PET and PET/CT is not a first-line test and reserved for equivocal
diagnostic cases. Use as a first-line study is not considered reasonable and
necessary.

6\. 18F-PET and PET/CT is not well-established to monitoring response to
treatment and use outside of diagnosis is not considered reasonable and
necessary with the exception cardiac sarcoidosis.

**_The following is not considered reasonable and medically necessary:_**  
The use of PET scan for inflammation and infection of other conditions not
specifically addressed above will be considered investigational.

Throughout the evidence review (18)F-fluorodeoxyglucose positron emission
tomography-computed tomography will be referred to as 18F-PET or 18F-PET/CT.

_Contractor Advisory Meeting (CAC)_

A CAC meeting on "Pet Scans for Inflammation and Infection" was held on
11/09/22 and subject matter experts (SMEs) reviewed pertinent literature and
provided input for the development of this policy. The transcripts and
recording are available in the CGS Administrators website:
https://www.cgsmedicare.com/partb/medicalpolicy/lcd_discussion_recordings.html.
Reference to the SME input will be included throughout the policy.

__

_Fever of Unknown Origin (FUO)_

Fever of unknown origin (FUO) in adults is defined as a temperature higher
than 38.3 degrees C (100.9 degrees F) lasting greater than three weeks with no
obvious source despite proper investigation.2,4 There are four categories of
potential etiology of FUO which are classic, nosocomial, immune deficient, and
human immunodeficiency virus-related. There are four subgroups of the
differential diagnosis of FUO are infections, malignancies, autoimmune
conditions, and miscellaneous.3 Physical examination, and standard laboratory
testing continue to be the clinical basis of the initial evaluation of the
patient with FUO.6,12

Chen et al. (2022) conducted a prospective study in a Chinese population to
identify the most suitable model for diagnosing patients with FUO based on
18F-PET/CT imaging.13 Patients were included if they were 14 years or older
and had a diagnosis of classical FUO who were hospitalized from January 2016
to July 2021. All patients underwent a standard diagnostic work up which
included a thorough patient history questionnaire, physical examination,
routine clinical investigation, and second-stage examinations (e.g.,
chest/abdominal CT with contrast, magnetic resonance imaging, nuclear medicine
techniques, and biopsy) and 18F-PET/CT scans when there were no diagnostic
clues. Final diagnosis was determined by the study team and causes were
divided into five (5) categories which included infection, noninfectious
inflammatory disease (NIID), malignancy, miscellaneous cause, and unknown
cause. 18F-PET/CT scans were attained using following the guidelines issued by
the Chinese Society of Nuclear Medicine. The median fever duration was 37 days
(21-732, range). The testing cohort resulted in AUCs of the infection
prediction model, the malignancy diagnostic model, and the noninfectious
inflammatory disease (NIID) prediction model were 0.89 (0.86-0.92), 0.94
(0.92-0.97), and 0.95 (0.93-0.97), respectively. The validation cohort
resulted in ACUs of 0.88 (0.82-0.93), 0.93 (0.89-0.98), and 0.95 (0.92-0.99),
respectively. Infectious diseases, tumors, NIIDs, and miscellaneous causes
were reported in 223, 121, 109, and 22 patients, respectively. At 6 month
follow up, 49 patients remained undiagnosed. Authors concluded 18F-PET/CT
diagnostic models displayed good performance, deeming it a reliable tool to
help discriminate the cause of FUO. They further acknowledge more robust
studies are needed.

Minamimoto 4 (2022) conducted a comprehensive review to help determine the
optimal use of 18F-PET/CT as a diagnostic tool in patients with FUO. Results
of 26 clinical studies (3 prospective and 23 retrospective) and meta-analysis
were reviewed for the diagnosis of FUO, sensitivity and diagnostic yield. It
was concluded that final diagnosis by 18F-PET/CT in patients with FUO was
dependent on the underlying disease. Earlier diagnosis has led to reduced
mortality rates in cases associated with infection such as staphylococcus
aureus bacteremia, Gram-positive bacteremia, and pacemaker or defibrillator
infection have been reported. Authors report the current status of 18F-PET/CT
applied to patients with FUO which may affect the future utilization to
improve FUO patient outcomes. This meta-analysis is limited by lack of high-
quality studies, combining observational and retrospective studies and absence
of RCTs.

Kubota et al. (2021) performed a multicenter prospective study to compare the
sensitivity of 18F-PET/CT with that of 67 Ga single photon emission computed
tomography (SPECT) for the identification of the site of greatest importance
for the final diagnosis of the cause of FUO. Ninety-one (91) 18F-PET/CT
results were assessed. The sensitivity of 18F-PET/CT (45%, 95% CI 33.1-58.2%)
was significantly higher than that for 67 Ga-SPECT (25%, 95% CI 15.5-37.5%) (P
= 0.0029) according to the patient-based assessments. Clinical impact of
18F-PET/CT (91%) was significantly higher than 67 Ga-SPECT (57%, P < 0.001).
Authors concluded 18F-PET/CT yielded superior sensitivity to 67 Ga-SPECT for
the identification of the site of greatest importance for the final diagnosis
of the cause of FUO.5

Letertre et al. (2021) performed a retrospective study to explore the
diagnostic contribution of the 18F-PET/CT in a population of patients with
classical FUO, to pinpoint its place in the diagnostic decision tree in a
real-life setting, and to identify those factors associated with a diagnostic
18F-PET/CT.14 Forty-four patients with FUO were included. Diagnoses were
obtained in 31 patients (70.5%), 17 had non-infectious inflammatory diseases,
9 had infections (20.5%), and 3 had malignancies (6.8%). 18F-PET/CT assisted
with making a final diagnosis (true positive) in 43.6% of all patients.
Sensitivity and specificity were 85% and 37%, respectively. A total of 135
investigations were performed prior to 18F-PET/CT including CT scans (93.2%)
and echocardiography (59.1%), and 108 after 18F-PET/CT mostly biopsies
(including the biopsy of a temporal artery) (25%) and MRIs (34%). Authors
concluded that 18F-PET/CT may be proposed as a routine initial non-invasive
procedure in the diagnostic workup of FUO, especially in anemic patients who
could be more likely to benefit from 18F-PET/CT.14

Buchrits et al. (2021) executed a single center retrospective cohort study to
assess the yield of 18F-PET/CT versus contrast enhanced CT (alone) for the
diagnosis of classical FUO.15 The 8-year study included 303 patients that
underwent 18F-PET/CT for FUO between 1/2012-1/2020. The final diagnosis was
based on clinical, microbiological, radiological, and pathological data
available in the patient's last follow-up (at least six months after
discharge). Each case was reviewed to determine if 18F-PET/CT was necessary,
or if diagnosis could have been attained by CT scan alone. 18F-PET/CT and CT
scan sensitivity and specificity results were reviewed. Final diagnosis was
achieved infectious disease 36.5% (111/303), malignancies 18.4% (56/303), and
non-infectious inflammatory conditions 17.1% (52/303). 18F-PET/CT scans had an
overall sensitivity of 88.7% and a specificity of 80.9% whereas CT scans were
75.2% and 90.2%, respectively.

Georga et al. (2020) performed a retrospective study at a tertiary academic
general hospital in Northern Greece in order to assess the diagnostic value of
18F-PET/CT in patients with FUO. Retrospectively reviewed 18F-PET/CT scans
performed on 50 consecutive adult patients referred for further investigation
of classic FUO. Histopathological and microbiological findings, clinical
criteria, or clinical follow-up were used to make final diagnosis in 39/50
(78%) of the patients. The cause of FUO was infection in 20/50 (40%),
noninfectious inflammatory diseases in 11/50 (22%), and malignancy in 8/50
(16%) patients. Fever remained unexplained in 11/50 (22%) patients. 18F-PET/CT
scan contributed to the diagnosis in 70% of the patients, by aiding in
identifying the underlying cause of FUO or by directing to the most
appropriate site for biopsy. Sensitivity, specificity, accuracy, positive
predictive value (PPV) and negative predictive value (NPV) of 18F-PET/CT FUO
for active disease detection in patients were 94.7%, 50.0%, 84.0%, 85.7%, and
75.0%, respectively. Authors concluded 18F-PET/CT was a sensitive method for
the detection of the underlying cause of FUO or directing to site for biopsy.
16

Kan et al. (2019) performed a meta-analysis to evaluate the diagnostic
performance of 18F-PET/CT in the diagnosis of Fever of unknown origin (FUO)
and inflammation of unknown origin (IUO). 17 A comprehensive literature search
was conducted and returned 23 studies comprised of 1927 patients. A per-
patient based analysis was calculated and a pooled diagnosis performance
yielded: sensitivity=0.84 (95% confidence interval [CI]=0.79- 0.89),
specificity =0.63 (95% CI=0.49-0.75), positive likelihood ratio=2.3 (95%
CI=1.5-3.4), negative likelihood ratio=0.25 (95% CI=0.16-0.38), diagnostic
odds ratio=9 (95% CI=4.0-20), and AUC=0.84 (95% CI=0.81-0.87). Authors
concluded 18F-PET/CT assists with identifying and excluding diseases, guiding
future diagnostic decisions, and circumventing unnecessary invasive
examinations in patients with non-specific symptoms. Limitations included
heterogeneity among included studies, limited data available for analysis and
high risk of selection bias. Authors report no conflicts of interest.

Lawal et al. (2019) retrospectively reviewed the scans of 46 patients to
evaluate the role of 18F-PET/CT in identifying the cause of FUO in patients on
renal replacement therapy (RRT) for end-stage renal disease (ESRD).18
18F-PET/CT assisted in identifying the cause of FUO in 22/46 patients
(47.83%). Infection resulted in fever in all 22 patients. According to
multiple regression analysis, the odds of a helpful 18F-PET/CT increased with
every unit increase in CRP level (OR: 1.009; 95% CI: 1.003-1.016; P=0.005).
Authors concluded 18F-PET/CT scans (22/46) identified the cause of FUO in
patients on RRT for ESRD with a higher CRP level being predictive of a
positive 18F-PET/CT outcome.

Kouijzer and colleagues (2018) conducted a review of current literature.
Pooled diagnostic yield was 56% (95% CI 50-61%), I2=61%, 18 studies and 905
patients. Only 5 studies reported results of previous imaging, and sub-group
analysis estimated diagnostic yield beyond conventional CT at 32% (95% CI
22-44%), I2=66%. Consensus was established that 18F-PET/CT is increasingly
available with an emerging role, but there is prevailing variability in
practice. Authors concluded that there was insufficient evidence to support
the value of 18F-PET/CT in investigative algorithms of FUO. There is a need
for research, involving prospective studies recruiting at diagnosis of FUO,
with updated case definitions and hard outcome measures. These studies are
vital for balancing both radiation exposure and costs against possible
benefits of utilizing 18F-PET/CT.19

Schonau et al. (2018) prospectively enrolled 240 patients of which 72 were
diagnosed with FUO, 142 with inflammation of unknown origin (IUO) and 26 had
FUO or IUO previously (exFUO/ IUO) to assess the diagnostic utility of
18F-PET/CT in patients with FUO or IUO and to define parameters that increase
the likelihood of diagnostic 18F-PET/CT.20 Final diagnosis was made in 190
patients (79.2%) in which 132 had NIID (69.5%), 27 had infections (14.2%), 20
malignancies (10.5%) and 11 other diseases (5.6%). 18F-PET/CT was helpful in
determining final diagnosis in 136 FUO patients. Chief diagnoses were adult-
onset Still's disease at 15.3% in the FUO group, large vessel vasculitis at
21.1% and polymyalgia rheumatica 18.3% in the IUO group then IgG4-related
disease (15.4%) in the exFUO/IUO group. Authors conclude that a more accurate
diagnosis was achieved in more than 50% of FUO and IUO cases with utilization
of 18F-PET/CT.

__

Takeuchi et al. (2018) performed a systematic review and meta-analysis to
assess the association of 18F-PET or PET/CT results with spontaneous remission
in classic fever of unknown origin.21 The search yielded nine studies of
PET/CT results (418 patients) and four studies of standalone PET results (128
patients). Negative PET/CT results were significantly more probable to present
with spontaneous regression than positive results (summary RR=5.6; 95% CI:
3.4-9.2; P<.001; I2=0%). Standalone PET results and spontaneous remission
yielded no significant association. As result of random-effects study-level
meta-regression, PET/CT results [relative RR (rRR)= 7.4; 95% CI: 2.5-21.3;
P=.002], compared with standalone PET results, and publication year (rRR=1.2
per 1 year; 95% CI: 1.0-1.3; P=.013) were significantly associated with
spontaneous remission. Authors concluded FUO patients with negative PET/CT
results yielded a high likelihood of spontaneous remission, but further
studies should be conducted to validate their findings. Limitations included
small sample size, limited data, inclusion of studies with high risk of bias,
retrospective study design, short follow-up period and variability in methods
across studies.

Bharucha et al. (2017) conducted a systematic review and meta-analysis to
assess the diagnostic yield of 18F-PET/CT in patients with fever of unknown
origin.22 After the quality assessment was performed, 18 studies with a total
of 905 patients were selected for meta-analysis. Eighteen studies (905
patients) resulted in a pooled diagnostic yield of 56% (95% confidence
interval [CI]: 50-61%, I2=61%). Previous imaging was only reported in five
studies, and diagnostic yield beyond conventional CT at 32% (95% CI: 22-44%;
I2=66%) was estimated from subgroup analysis. Authors conclude although
consensus was established that 18F-PET is becoming more available and has an
emerging role, there is high variability in practice and resolve there is
insufficient evidence to support 18F-PET/CT in investigative algorithms of
FUO. Limitations included studies with a high risk of bias, significant
heterogeneity, and overall low quality.

Hung et al. (2017) prospectively evaluated 68 patients with a diagnosis of FUO
to compare the efficacy of 18F-PET and 67Ga SPECT/CT in diagnosing FUO on a
head-to-head basis. First-step examinations included Clinical history,
physical examinations, routine laboratory tests , chest radiographs (including
CT in nine patients), and abdominal ultrasound were assessed, but yielded no
potentially diagnostic clues. The patients were entered prospectively into the
study. As a second step investigation technique, 18F-PET and 67Ga SPECT/CT,
was performed within a 7-day interval. All studies were read and interpreted
independently by two board-certified nuclear medicine physicians. Ten of the
68 patients were excluded. In 23 patients an underlying infectious disease was
found, 10 patients had a malignant disorder, 11 patients had non-infectious
inflammatory disease, two patients had adrenal insufficiency. The cause of FUO
was not found for 12 patients. A high false-positive rate of 44% (7/16) was
observed for 18F-PET/CT, while a high false-negative rate of 55% (23/42) was
observed for 67Ga SPECT/CT. 18F-PET/CT studies depicted all 67Ga-avid lesions.
The sensitivity (79% vs. 45%) and clinical contribution (72% vs. 55%) of 18F
PET/CT in diagnosing FUO were significantly higher than those of 67Ga SPECT/CT
(p < 0.05). Authors concluded the diagnostic performance of 18F-PET/CT was
superior to 67Ga SPECT/CT in the work-up of patients with FUO. With its rapid
results and superior sensitivity, 18F-PET/CT may replace 67Ga SPECT/CT where
this technique is available. 23

Takeuchi et al. (2016) performed a meta-analysis to review the test
performance, diagnostic yield, and management decision impact of nuclear
imaging tests in patients with classic FUO.24 The literature search included
42 studies comprised of 2,058 patients. Studies with higher prevalence of
neoplasms and infections resulted in higher diagnostic yields. Nonneoplastic
causes were found to be less successfully localized. Among the four imaging
modalities, 18F-PET/CT resulted in the best test performance and diagnostic
yield with summary sensitivity was 0.86 (95% confidence interval [CI],
0.81-0.90), specificity 0.52 (95%CI, 0.36-0.67), and diagnostic yield 0.58
(95% CI, 0.51-0.64). Authors concluded nuclear imaging tests, predominantly
18F-PET/CT, may be helpful in identifying sources of fever in patients with
classic FUO. They acknowledge studies with standardized diagnostic algorithms
are needed to establish optimal timing for testing and further assessments are
needed to fully understand management decision impacts and outcomes.
Limitations include heterogeneity, small sample size, methodologic
limitations, and a lack of standardization of diagnostic algorithms.

Besson et al. (2016) conducted a stratification based meta-analysis to
quantify the contribution of 18F-PET/CT to the diagnostic assessment of fever
of unknown origin (FUO). PubMed/MEDLINE was searched from 2000 to September
2015 for articles with inclusion criteria of: (1) FUO as the initial
diagnosis, (2) no immunosuppressed or nosocomial condition, (3) final
diagnosis not based on 18F-PET/CT, (4) a follow-up period specified, (5) adult
population, and (6) availability of adapted data for calculation of odds
ratios (ORs). Ultimately, 14 studies were included in the meta-analysis.
Statistical analysis and sensitivity analyses were performed. Authors
concluded that "normal 18F-PET/CT findings led to an increase in the absolute
final diagnostic rate of 36% abnormal 18F-PET/CT findings to an increase of
83%, corresponding to a pooled OR of 8.94 (95% CI 4.18-19.12, Z=5.65;
p<0.00001)." They further state that the design of the studies also influenced
results as follows: (OR 2.92, 95% CI 1.00-8.53 for prospective studies; OR
18.57, 95% CI 7.57-45.59 for retrospective studies; p= 0.01). Authors
concluded that geographic area and length of follow up did not influence study
results and increased final diagnostic rate in FUO was associated with
abnormal 18F-PET/CT findings. Further randomized prospective studies with
standardized 18F-PET/CT procedures are needed. Limitations include
heterogeneity among included studies, lack of diagnostic protocol and possible
selection bias.25

Pereira et al. (2016) conducted a retrospective study on 76 consecutive
patients to determine the clinical usefulness of 18F-PET/CT for FUO and to
define determinants of its diagnostic utility. 18F-PET/CT exhibited
characteristically increased 18F activity in 56 patients (74%), leading to
confirmation of, or change in, the suspected cause of FUO in 57 and 17%,
respectively. Final diagnosis in 18F-PET/CT patients included infection (21%),
malignancy (22%), noninfectious inflammatory disease (12%), others (5%), or an
unknown cause (40%). The success rate, sensitivity, and specificity of
18F-PET/CT were 60, 77, and 31%, respectively. Patients with suspected
malignancy (100%, 95% confidence interval 79-100%) produced the highest
sensitivity. Diagnostic performance was independent of the investigated
variables apart from suspected infection as a cause of FUO (odds ratio 0.1,
95% confidence interval 0.01-0.8, P=0.033). The authors recognize most studies
investigating 18F-PET/CT in patients with FUO are difficult to compare based
on heterogeneity of the patient population, variation among 18F-PET/CT
techniques, and the stages at which it was performed. This study's findings
yielded a success rate of 61% and a sensitivity of 77% in FUO patients.
However, they go further and state a final diagnosis remained unclear in 39%
of the FUO patients despite performing an 18F-PET/CT.26

Gafter-Gvili (2015) conducted a retrospective single center study over 4 years
on 112 patients that were hospitalized in the years 2008-2012 for FUO
evaluation and underwent 18F-PET/CT.27 Final diagnosis was based on clinical,
microbiological, radiological, and pathological data available at the final
follow-up. A total of 83 patients (74%) resulted in a final diagnosis which
included: infectious disease 43% (n=49), non-infectious inflammatory disease
16% (n=17), malignancies 14% (n=15) and other diagnosis in 1.7% (n=2).
18F-PET/CT were considered helpful in 66% (74 studies) and contributed to 46%
of positive diagnosis and 20.5% exclusion of diagnosis. 18F-PET/CT
demonstrated a sensitivity of 72.2%, a specificity of 57.5%, a positive
predictive value (PPV) of 74.2% and a negative predictive value (NPV) of
53.5%. FUO spontaneously resolved in 20% of patients without a diagnosis.
Authors concluded support for 18F-PET/CT as the most important imaging
modality based on their study findings reporting 66% of studies were
contributory to diagnosis in patients with FUO.

Hao and associates (2013) performed a meta-analysis to assess the diagnostic
performance of 18F-PET/CT in patients with fever of unknown origin. 28 Fifteen
studies comprised of 595 patients with FUO were included. On a per-patient-
based analysis, a pooled sensitivity of 18F-PET/CT in detecting the cause of
FUO was 85% (95% confidence interval 81-88%). The area under the receiver-
operating characteristic curve was 0.88. Authors concluded that 18F-PET/CT
demonstrated high sensitivity and value in diagnosis of patients with FUO.
They further stated 18F-PET/CT is an accurate technique in this setting, but
the possibility of false-positive results should be considered outside of this
setting. Limitations resulted from inclusion of studies of low to moderate
quality, bias, limited sample size.

Dong et al. (2011) conducted a meta-analysis to evaluate the value of
18F-PET/CT in patients with fever of unknown origin.29 Five 18F-PET studies
and four 18F-PET/CT studies were evaluated. For the detection of FUO, 18F-PET
resulted in a pooled sensitivity and specificity were 0.826 (95% CI;
0.729-0.899) and 0.578 (95% CI; 0.488-0.665), respectively, and the AUC was
0.810. Among the results of 18F-PET studies severe heterogeneity was present
(QSE=12.40, I2=67.7%; QSp=35.98, I2 =88.9%). Pooled sensitivity and
specificity of 18F-PET/CT were 0.982 (95% CI; 0.936-0.998) and 0.859 (95% CI;
0.750-0.934), respectively, and the AUC was 0.947. No statistical differences
were observed in the AUC and Q* index between FDG-PET and 18F-PET/CT (Z =
0.566, p > 0.05). Limitations of this meta-analysis include incorporation of
studies with poor design, small number of studies with limited sample sizes,
and possible bias.

Keidar and associated (2008) conducted a study to prospectively assess the
role of PET/CT using 18F in the investigation of FUO. A total of 48
consecutive patients (25 men, 23 women; age range, 24-82 yo) with FUO
underwent 18F-PET/CT scans. Final diagnosis was based on histopathology,
microbiologic assays, or clinical and imaging follow-up. 18F-PET/CT detected
suggestive foci of increased 18F uptake in 27 patients. In 22/27 positive
studies (81%), 18F-PET/CT identified the underlying disease and diagnosed
infection in 9 patients, an inflammatory process in 10 patients, and
malignancy in 3 patients. 18F-PET/CT was negative in 21 patients. All these
patients were diagnosed as having systemic non focal infection or drug-induced
fever or showed spontaneous resolution of the febrile state with no evidence
of a localized inflammatory, infectious, or malignant process for a clinical
follow-up period of 12-36 mo. Authors concluded-18F-PET/CT identified the
underlying cause of the fever in 46% of the present study population and
contributed to the diagnosis or exclusion of a focal pathologic etiology of
the febrile state in 90% of patients. 18F-PET/CT has a high negative
predictive value (100%) for assessment of FUO.30

Bleeker-Rovers (2007) conducted a prospective multicenter study to integrate
the use of 18F-PET as part of a diagnostic protocol in the general FUO patient
population.31 Patients with FUO were recruited from a university hospital and
five community hospitals. A total of 70 patients were enrolled at a university
hospital (n=38) and five community hospitals (n=32). A diagnostic protocol
utilizing 18F-PET was employed. 33% of scans contributed to the final
diagnosis and 70% of abnormal 18F-PET scans were clinically helpful, however,
the probability of reaching a diagnosis was only 50%. 18F-PET had a
sensitivity of 88% and a specificity of 77%, with a positive predictive value
of 70% and negative predictive value of 92%. There was no significant
difference between patents diagnosed in the university hospital versus the
community hospitals and the patients with normal erythrocyte sedimentation
rate (ESR) and C-reactive protein (CRP) 18F-PET proved not to be helpful.
Authors concluded that 18F-PET, when included in a diagnostic protocol, could
be a useful imagining modality in patients with FUO and raised ESR or CRP.

Jaruskova and Belohlavek (2006) retrospectively reviewed 124 patients with
fever of unknown origin (76%) or prolonged fever due to a suspected post-
surgical infection of a joint or vascular prosthesis (24%). Fifty-seven (46%)
patients had positive 18F-PET findings. In six patients, no further clinical
information was available. Positive 18F-PET findings in 51 patients and 118
patients in total were subsequently evaluated. Systemic connective tissue
disease was confirmed in 17 patients, lymphoma in three patients, inflammatory
bowel disease in two patients, vascular prosthesis infection in seven
patients, infection of a hip or knee replacement in seven patients, mycotic
aneurysm in two patients, abscess in four patients and AIDS in one patient.
Eight (16%) patients the finding was falsely positive. Authors concluded
18F-PET or 18F-PET/CT contributed to establishing a final diagnosis in 84% of
the 51 patients with positive 18F-PET findings and in 36% of all 118 evaluated
patients with prolonged fever.32

Mourad and colleagues (2003) performed a systematic review to develop
evidence-based recommendations for the diagnostic workup of FUO. The quality
of articles was rated as "good," "fair," or "poor,". Sensitivity, specificity,
and diagnostic yield of tests were calculated. Eleven studies indicate that
diseases include "no diagnosis" (19%), infections (28%), inflammatory diseases
(21%), and malignancies (17%). Deep vein thrombosis (3%) and temporal
arteritis in the elderly (16%-17%) were considered. Four good studies indicate
that patients with undiagnosed FUO recover spontaneously (51%-100%). A single
fair-quality study yielded a high specificity (99%) for the diagnosis of
endocarditis in FUO by applying the Duke criteria. One fair-quality study
showed that computed tomographic scanning of the abdomen had a diagnostic
yield of 19%. Ten studies of nuclear imaging revealed that technetium was the
most promising isotope, showing a high specificity (94%), albeit low
sensitivity (40%-75%) (2 fair-quality studies). Two fair quality studies
showed liver biopsy to have a high diagnostic yield (14%-17%), but with risk
of harm (0.009%-0.12% death). Empiric bone marrow cultures showed a low
diagnostic yield of 0% to 2% in two articles rated as fair quality. Authors
concluded that diagnosis of FUO may be assisted by the Duke criteria for
endocarditis, computed tomographic scan of the abdomen, nuclear scanning with
a technetium based isotope, and liver biopsy (fair to good evidence). Routine
bone marrow cultures are not recommended.33 Of FUO patients, 18F-PET/CT was
deemed as necessary in 26% (79/303). Endovascular infection, hematological
malignancy, and large vessel vasculitis were the only factors associated with
18F-PET/CT necessity on multivariable analysis. Authors concluded they were
able to successfully define the patient and conditions where referral for
18F-PET/CT would be the first in line imaging modality in cases such as
hematological malignancies, LVV and endovascular infections. They acknowledge
the need for more robust studies comparing 18F-PET/CT and CT scan as a first
line diagnostic tool.

_Additional Guidance_

UpToDate states that F-fluorodeoxyglucose positron emission tomography
(18F-PET) may be sensitive in identifying anatomic sites of inflammation and
malignancy. 18F-PET may have a valuable place in the evaluation of FUO, but
additional data are needed to determine its added value beyond repeated
clinical evaluation over time and routine CT.2

**__**

A 2022 review paper published in the New England Journal of Medicine provides
a summary of fever of unknown origin and includes a diagnostic and management
algorithm for FUO.6 This algorithm includes 18F-PET/CT after history and
physical and minimal and advance FUO evaluation fails to determine a
diagnosis. The author reports the range of performance for 18F-PET/CT with
sensitivities ranging from 52-85% and diagnostic yield  50% which is 30%
higher than conventional CT. The yield seems to higher in patients with
infection or neoplasia as compared to autoimmune sources. They also state PET
scan seems to be superior to other nuclear imaging methods such as PET without
CT, or gallium or leukocyte scintigram.21

The SMEs felt there is a role for PET scan for FUO citing it can be useful in
20-30% of cases to identify the source of FUO in cases that meet the
definition above (3 weeks of unexplained fever). The addition of CT may
increase yield by 30%. They report pooled sensitivity between 75-86% based on
current literature. They also discussed the value of a negative study in which
literature shows a higher rate of spontaneous resolution of fever allowing
providers to feel more confident in a watchful waiting approach. The discussed
limitations such as recent post-operative changes, antibiotic and steroid use,
and importance of standardized protocols. Overall, they felt there is role for
this study in FUO as they consider this equivalent to superior to other
studies used in these diagnostic conundrums with faster results.

**__**

**_Cardiac_**

**__**

Preparation is critically important for the success of cardiac PET/CT. The
SMEs explained there are standardized protocols that must be followed to get
useful results from the study. These protocols are well established and
readily available.8,9

__

_Infections: Cardiac Endocarditis and Infected Cardiac Implantable Devices_

Infective endocarditis (IE) is an infection of the endocardial surface of the
heart. Frequently including the heart valves, predominantly prosthetic heart
valves. IE has an annual incidence of 3-9 cases per 100,000 with the highest
levels reported in patients with prosthetic valves, cardiac devices,
unrepaired cyanotic heart disease and those with a family history.34

A report by the American College of Cardiology/American Heart Association
Joint Committee on Clinical Practice Guidelines released in 2020 recommends in
patients with suspected endocarditis, it is recommended that the Modified Duke
Criteria are to be utilized as the current standard for diagnosis. 35 This
criterion incorporates the use of clinical, imaging, and bacteriological
criteria. Recommendation 12.2 states "In patients classified by Modified Duke
Criteria as having "possible IE," 18F-PET/CT is reasonable as adjunct
diagnostic imaging." They go further to state "18F-PET/CT may also be
considered a complementary diagnostic tool for some patients with suspected
native valve endocarditis." This recommendation is supported at the CCF/AHA
Task Force on Practice Guidelines. Methodology Manual and Policies From the
ACCF/AHA Task Force on Practice Guidelines at level of 2A which is a moderate
strength of recommendation and considered reasonable.

__

UpToDate published a topic on the clinical manifestations and evaluation of
adults with suspected left-sided native valve endocarditis.36 It recognizes
echocardiography as the standard imaging modality for evaluation of cardiac
valves however, 18F-PET/CT has emerged as a diagnostic tool for IE that can
identify infection of native valves, paravalvular areas and extracardiac sites
of infection.

A 2015 ESC Guidelines for the management of infective endocarditis: The Task
Force for the Management of Infective Endocarditis of the European Society of
Cardiology (ESC) Endorsed by: European Association for Cardio-Thoracic Surgery
(EACTS), the European Association of Nuclear Medicine (EANM)10 recommends "in
the setting of the suspicion of endocarditis on a prosthetic valve, abnormal
activity around the site of implantation detected by 18F-PET/CT (only if the
prosthesis was implanted for >3 months) or radiolabeled leucocyte SPECT/CT
should be considered a major criterion."

The Royal College of Physicians published a contemporary update infective
endocarditis in 2020. 18F-PET/CT or radiolabeled leucocyte single photon may
assist as an adjunctive investigation to determine presence of inflammation or
infection of the prosthetic heart valve that would result in an IE diagnosis.
Whereas in cases of perivalvular pathology especially when root abscess or
aortic valve endocarditis is suspected, CT was determined to be of value.37

The National Heart Association of Malaysia (NHAM) and the Academy of Medicine
Malaysia produced a clinical practice guideline for prevention, diagnosis and
management of infective endocarditis in 2017 (reviewed in 2021). Guidelines
suggest when used as an adjunct modality, WBC SPECT/CT and 18F-PET/CT may have
a role in detecting peripheral embolic, metastatic infectious lesions, cases
with high clinical suspicion of IE, prosthetic valve endocarditis and in other
difficult cases.

Albano et al. (2021) conducted a systematic review and meta-analysis to assess
the diagnostic role of 18F-PET/CT imaging in native valve endocarditis
(NVE).38 Twelve papers were included in the analysis comprised of 600 patients
with NVE. 18F-PET/CT imaging resulted in a pooled sensitivity of 31% (95%
confidence interval [CI]: 26% to 36%) with a heterogeneity (I2=73.1%; p =
0.001) and a pooled specificity was 82% (95% CI: 77% to 86%) with a
heterogeneity (I2 = 59%; p = 0.012). Authors conclude 18F-PET/CT imaging in
NVE remains suboptimal. This is attributed to the low accuracy heterogeneity
among papers, despite good specificity (82%). They further state specific
protocols may improve diagnostic performance. Limitations include selection
bias, small sample size, low study quality and design, and high heterogeneity.

De Camargo (2020) published a prospective study of 303 patients with left
sided infective endocarditis (IC) who underwent 18F-PET/CT. Of the 188 in this
population with prosthetic valves the sensitivity, specificity, and positive
and negative predictive values of 18F-PET/CT focal uptake were 93%, 90%, 89%,
and 94%, respectively. Among 115 patients with native valve endocarditis, the
corresponding values were 22%, 100%, 100%, and 66%. The authors concluded the
use of 18F-PET/CT increased the diagnostic capability of the modified due
criteria in the setting of prosthetic valves. in the setting of native valves,
it was found to be less accurate and could only be considered a complementary
diagnostic tool for those with persistent suspicion of IE but inconclusive
results.39

Mahmood et al. (2019) conducted a meta-analysis of 13 studies including 537
patients performed to evaluate the role of 18F-PET/CT as an adjunctive
diagnostic test for prosthetic valve endocarditis and culture negative
endocarditis. The pooled sensitivity of 18F-PET/CT for diagnosis of IE was
76.8% (95% CI 71.8-81.4%; Q 5 39.9, P < 0.01; I2 5 69.9%) and the pooled
specificity was 77.9% (95% CI 71.9-83.2%; Q 5 44.42, P < 0.01; I2 5 73.0%).
Diagnostic accuracy was improved with prosthetic valves with a sensitivity of
80.5% and specificity of 73.1%. Additional extracardiac foci of infection were
found in 17% of patients on whole body 18F-PET/CT. The authors concluded that
18F-PET/CT is a useful adjunctive diagnostic tool in the evaluation of
diagnostically challenging cases if IE especially those with prosthetic
valves. Limitations of this study is moderate heterogeneity including
variation in imaging protocols, data acquisition and methodological concerns
in included studies including lack of blinding. The authors also address the
uncertainty of the impact of prior antibiotic treatment on the sensitivity of
18F-PET/CT and call for additional prospective studies.40

Juneau et al. (2017) performed a systematic review and meta-analysis to
systematically assess the diagnostic accuracy of 18F-PET/CT, labeled leukocyte
scintigraphy (LS), and Gallium-67 citrate scintigraphy for the diagnosis of
CIED infection.41 Literature was systematically reviewed on the three
modalities in CIED infection identifying 2493 articles in which 13 articles
(11 studies for 18F-PET/CT and 2 for LS), were ultimately selected for
analysis. The meta-analysis on the use of 18F-PET/CT resulted in a sensitivity
of 87% (95% CI, 82%-91%), a specificity of 94% (95% CI, 88%-98%) and an AUC of
0.952. There was insufficient data for LS therefore meta-analysis was not
performed. Authors concluded that 18F-PET/CT and LS may be useful for the
diagnosis of CIED infection and suggest that 18F-PET/CT may be preferred when
available. Limitations include lack of gold standard for diagnosis of CIED,
lack of blinding, possible selection bias and heterogenous methods data. A
similar 2018 review and meta-analysis to evaluate the potential utility of
18F-PET/CT, (67) Ga citrate and radiolabeled white blood cell (WBC)
scintigraphy in the diagnosis of IE.42 reported on 14 studies with sensitivity
81% for 18F-PET/CT and 86% for LS again concluding both tests are accurate for
diagnosis of IE.42

Yan et al. (2016) performed a systematic review and meta-analysis to assess
the role of 18F-PET/CT in patients with infectious endocarditis (IE).43 The
literature search returned 6 studies (2 retrospective and 4 prospective
studies) comprised of 246 patients. The meta-analysis yielded a pooled
sensitivity of 61% (95% confidence interval (CI), 52 - 88%), and a pooled
specificity of 88% (95% CI, 80 - 93%). Authors concluded due to its low
sensitivity, 18F-PET/CT is currently not sufficient for the diagnosis of IE,
however, it might be a useful in the diagnosis of prosthetic valve
endocarditis (PVE) and skin and pocket cardiovascular implantable electronic
device (CIED) infections. Limitations include bias, selection of studies with
low to moderate quality with small sample sizes, lack of testing for
heterogeneity due to limited number of studies and use of suboptimal reference
tests in selected studies.

Pizzi et al. (2015) performed a prospective study at a cardiac surgery
referral center to evaluate the clinical value of 18F-PET/CT and 18F-PET/CTA
for the diagnosis of IE in patients with prosthetic valves or intracardiac
devices.44 The cardiac surgery referral center was comprised of a
multidisciplinary IE unit including cardiologists, infectious diseases
physicians, cardiac imaging specialists, heart surgeons, neurologists, and
microbiologists. A total of 92 patients with prosthetic valves or cardiac
devices consecutively admitted for suspected IE were evaluated in this study.
Patients underwent echocardiography and 18F-PET/CT and 76 patients had cardiac
CTA. Findings were compared and yielded concordant results in 54% of cases
(K=0.23). Comparisons were evaluated between final diagnostic consensus and
initial diagnosis with DC at admission, 18F-PET/CT, and Duke Criteria
(DC)+18F-PET/CT. Reclassification of 90% of cases resulted from DC+18F-PET/CT
that were initially classified as possible IE. "Sensitivity, specificity, and
positive and negative predictive values were 52%, 94.7%, 92.9%, and 59.7% for
DC; 87%, 92.1%, 93.6%, and 84.3% for 18F-PET/CT; and 90.7%, 89.5%, 92%, and
87.9% for DC+18F-PET/CT. Use of 18F-PET/CTA yielded better diagnostic values
than PET/nonenhanced CT (91%, 90.6%, 92.8%, and 88.3% versus 86.4%, 87.5%,
90.2%, and 82.9%) and reduced the rate of doubtful cases from 20% to 8%
(P<0.001). DC+18F-PET/CTA reclassified an additional 20% of cases classified
as possible IE with DC+PET/nonenhanced CT. In addition, 18F-PET/CTA enabled
detection of a significantly larger number of anatomic lesions associated with
active endocarditis than PET/nonenhanced CT (P=0.006) or echocardiography
(P<0.001)." Authors concluded "18F-PET/CT improves the diagnostic accuracy of
the modified DC in patients with suspected IE and prosthetic valves or cardiac
devices. 18F-PET/CTA yielded the highest diagnostic performance and provided
additional diagnostic benefits." Limitations include lack of gold standard,
and authors bring up concern regarding radiation exposure resulting from the
imaging examination

__

Saby et al. (2013) conducted a prospective study to determine the value of
18F-PET/CT for diagnosing prosthetic valve endocarditis (PVE).45 A total of 72
consecutive patients suspected of having PVE were included. All subjects
underwent clinical, microbiological, and echocardiographic evaluation and
cardiac 18F-PET/CT at admission. At a 3 month follow up the final diagnosis
was defined according to the clinical and/or pathological modified Duke
criteria. Abnormal 18F uptake around the prosthetic valve was seen in 36 (50%)
subjects. Sensitivity, specificity, positive predictive value, negative
predictive value, and global accuracy were (95% confidence interval): 73% (54%
to 87%), 80% (56% to 93%), 85% (64% to 95%), 67% (45% to 84%), and 76% (63% to
86%), respectively. A significant increase in the sensitivity of the modified
Duke criteria at admission (70% [52% to 83%] vs. 97% [83% to 99%], p = 0.008)
was observed when abnormal FDG uptake around the prosthetic valve as a new
major criterion was added. Yielding a significant reduction in the number of
possible PVE cases from 40 (56%) to 23 (32%). Authors concluded 18F-PET/CT was
a useful imaging modality in diagnosing PVE and study results support adding
abnormal FDG uptake as a major criterion for PVE. Limitations include presence
of false positive and false negative tests, defining optimal timing for
performing 18F-PET/CT, use of modified Duke criteria at the end of the follow-
up was used as the gold standard in this study, and short follow up period.

Diagnosis of cardiac implantable electronic device (CIED) can be challenging.
Echocardiogram is currently the first line imaging technique in patients with
suspected CIED but is of limited value unless there is vegetation visualized
along the lead. This has led to further investigation of the role of PET scan
because this is an infective process. 41 Alternative studies are somewhat
limited in this population because MRI is often contraindicated in patients
with CIED.

Juneau et al. (2017) conducted a systematic review and meta-analysis which
included 11 studies on use of 18F-PET/CT for cardiac implantable electronic
device (CIED) infections with 260 patients. This analysis also included
studies for labeled leukocyte scintigraphy (LS), and Gallium-67 citrate
scintigraphy. They report pooled sensitivity of 18F-PET/CT was 87% (95% CI,
82-91%) and specificity of 94% (95% CI, 88-98%). The authors conclude that
18F-PET/CT yields a high sensitivity specificity and accuracy and is useful in
the diagnosis of CIED infections. 41

__

_Cardiac Sarcoidosis (CS)_

__

Cardiac sarcoidosis is rare, affecting 10 out of 100,000 people a year. CS is
estimated to affect 2-5% of those with systemic disease although autopsy
studies suggest it may be as high as 20-27%. In a joint SNMMO-ASNC expert
consensus document on the role of 18F-PET/CT in cardiac sarcoid detection and
therapy monitoring. Cardiac sarcoidosis may be present in as many as 20% of
sarcoid cases, may be asymptomatic, and is a major cause of death from this
condition. CS remains an underdiagnosed condition and prognosis may be
improved with treatment. Diagnosis is challenging given the low yield of
extracardiac tissue biopsy and no useful gold standards. Cardiac 18F-PET Has
been increasingly added to diagnostic algorithms for CS to detect cardiac
involvement as well as assessing the presence and severity of myocardial
inflammation when done in patients without contraindication and with proper
preparation.11

A Joint Procedural Position Statement on Imaging in Cardiac Sarcoidosis. From
the Cardiovascular and Inflammation & Infection Committees of the European
Association of Nuclear Medicine (EANM), the European Association of
Cardiovascular Imaging (EACVI), and the American Society of Nuclear Cardiology
(ASNC)(2017) reports "FDG-PET has emerged as a powerful and most commonly used
technique not only to assess the extent of systemic sarcoidosis but also to
assess extent and activity of myocardial involvement". The panel recommends
18F-PET in conjunction with radionuclide myocardial perfusion imaging (MPI) is
therefore the currently recommended radionuclide method for evaluation of
cardiac sarcoidosis. The sensitivity for detecting CS in the reviewed studies
was 85-100% (39-100% range). This is consistent with other SR/MA which report
similar range.11

Aiken et al. (2022) conducted a systematic review and meta-analysis on the
diagnostic accuracy of cardiac MRI versus 18F-PET/CT for CS. Thirty-three
studies including 678 patients with CS were included. Six studies offered a
direct comparison between cardiac MRI and 18F-PET/CT in the same 303 patients.
Cardiac MRI had a higher sensitivity than 18F-PET/CT (95% vs 84%; P = .002)
with no difference in specificity. This study was limited by high risk of bias
in 30 of the studies included and few studies with direct comparison.46

Kim et al. (2020) 47 conducted a systematic review and meta-analysis which
includes 17 studies with 891 patients with CS. They a report pooled
sensitivity of 0.84 [95% confidence interval (95% CI) 0.71-0.91] with
heterogeneity (I2 = 77.5) and a pooled specificity of 0.83 (95% CI 0.74-0.89)
with heterogeneity (I2 = 80.0). Meta-regression suggests the heterogeneity was
caused by studies which combined 18F-PET/CT with myocardial perfusion studies.
The authors acknowledge the limited studies on use of 18F-PET/CT for CS and
need for further large multicentered studies. The suggested addition of
myocardial perfusion imaging may improve diagnostic accuracy.

A 2020 review describes the importance of appropriate preparation and protocol
for accurate 18F-PET/CT results, they describe 18F-PET/CT as the "primary
tool" to assess active inflammation and a powerful complementary modality in
cases where diagnosis remains uncertain despite initial investigation
including cardiac MRI. They describe the ability of 18F-PET/CT to assess the
degree of CS involvement and aid in guiding the course of therapy as well as
identification of extracardiac disease that can be potential targets for
biopsy. The authors also reference studies in which reclassification occurred
after the study improving diagnostic accuracy.48

Vita et al (2018) conducted a retrospective review of 107 consecutively
enrolled subjects referred for cardiac sarcoidosis (CS) evaluation.49
Evaluations of CS were conducted by cardiac magnetic resonance (CMR) and
18F-PET/CT to determine the value of combining them in assessing the
likelihood of CS and guiding patient management. Two blinded experienced
readers assessed the likelihood of CS after reviewing CMR and 18F-PET images.
Outlined by predefined criteria, readers were asked to categorize the
likelihood of CS as no (<10%), possible (10%-50%), probable (50%-90%), or
highly probable (>90%). A total of 107 patients (age, 5511 years; left
ventricular ejection fraction, 4316%), 91 (85%) had late gadolinium
enhancement, whereas 82 (76%) had abnormal F18-fluorodeoxyglucose uptake on
18F-PET, which was suggestive of active inflammation. A total of 91 patients
with positive late gadolinium enhancement, 60 (66%) had abnormal
F18-fluorodeoxyglucose uptake. When 18F-PET and CMR were combined, 48 (45%)
patients were reclassified as having a higher or lower likelihood of CS, most
of them (80%) being correctly reclassified when compared with the final
diagnosis. In patients with highly probable CS, immunosuppressive therapies
were significantly more likely to change. Combining CMR and 18F-PET resulted
in the reclassification to highly probable (>90%) likelihood in 12 new
patients. Authors concluded results show that including data from both CMR and
18F-PET may increase the diagnostic certainty, chiefly following inconclusive
CMR or 18F-PET imaging.

Osbourne et al. (2014) aimed to determine if monitoring CS with 18F-PET/CT
improved outcomes, specifically ejection fraction (EF). This was a small
prospective study with 23 patients with cardiac sarcoidosis followed for a
total of 90 serial 18F-PET/CT scans averaging 4 scans per patient. In this
study they found that a reduction in the intensity and extent of myocardial
inflammation seen on the 18F-PET/CT was associated with improvements in the
EJ. Therefore, the authors concluded that serial 18F-PET/CT may be helpful in
titration of immunosuppressive therapy for improvement or prevention of heart
failure in CS.50

In another small observational study with 12 patients followed with 18F-PET/CT
before and after treatment with infliximab demonstrated that the detection of
changes on the 18F-PET/CT correlated with the clinical improvement in 92% of
these patients supporting the role of 18F-PET/CT for evaluation of response to
treatment. This is limited by the small sample size and lack of comparative
group.51

__

_Vascular Graft infection_

__

Pelletier-Galarneau et al. (2020) 52 published an editorial discussing
improving diagnosis with imaging in regard to vascular graft infections.
Historically, clinical manifestations of VGI are challenging. To add to the
complexity, there are various vascular prostheses and techniques that may
impact treatment outcomes of VGI. While CTA and MRI can be utilized in these
cases, they have their limitations. The combination of these challenges led to
the Management of Aortic Graft Infection (MAGIC)53 producing a criterion for
the diagnosis of aortic graft infection in 2016. Several small studies and
three meta-analyses on the use of 18F-PET in the diagnosis of VGI have been
investigated. 18F-PET for the detection of VGI yielded similar results
including a pooled sensitivity of 93%, 95%, and 96% and a pooled specificity
of 74%, 78%, and 80%. The gold standard for diagnosis may not always be
readily available therefore, it is suggested 18F-PET/CT coupled with the MAGIC
criteria may serve as a desirable technique to detect vascular graft
infection. Authors acknowledge the need for more robust studies to establish
the diagnostic accuracy and impact of 18F-PET/CT in the evaluation and
management of VGI patients.

Bowles et al. (2020) 54 performed a prospective cohort study to determine the
diagnostic yield of 18F-PET/CT in patients with suspected PVGI. A total of 49
patients with suspected prosthetic vascular graft infection (PVGI) were
included. Uptake patterns were defined as: (i) focal, (ii) patched (PVGI
criteria), and (iii) diffuse (no PVGI criterion). 18F-PET/CT values were
sensitivity (88%), specificity (79%), positive predictive values (67%), and
negative predictive value (93%). 18F-PET/CT successfully identified 14/16 PVGI
cases resulting in a focal (n = 10) or patched pattern (n = 4), with a true
negative in 26/33 cases with either a diffuse pattern (n = 16) or without
uptake (n = 10). A patched pattern occurred in 71% (5/7) false positive cases,
all of which were associated with all applications of adhesives for PVG
placement. Authors concluded results have established 18F-PET/CT as a useful
technique for the diagnosis of PVGI. They further recognized that adhesives
that were applied for PVG placement resulting in a patched pattern on
18F-PET/CT does not indicate infection.

__

Rojoa and associates conducted (2019) 55 a systemic review and meta-analysis
were performed to evaluate the diagnostic accuracy of 18F-PET/CT in vascular
prosthetic graft infection (VPGI) cases. A total of 433 prostheses were
identified in 12 studies. Of those 433, 202 were infected. 18F-PET and
18F-PET/CT were used to analyzed five different methods including: graded
uptake, focal uptake, maximum standardized uptake value (SUVmax), tissue to
background ratio (TBR), and dual time point (DTP). Pooled estimates were
graded based on sensitivity and specificity uptake. Authors concluded
18F-PET/CT demonstrated a high sensitivity when used as a diagnostic tool for
VPGI. They note accuracy could be increased by the addition of CT with PET.

__

Husmann et al. (2018) 56 produced a prospective study that included subjects
from the prospective Vascular Graft Infection Cohort Study (VASGRA) if they
had microbiologically proven AGI to evaluate the role of 18F-PET/CT in the
long-term monitoring of patients. Metabolic activity in 18F-PET/CT was
quantified by using maximum standardized uptake value (SUVmax) and was further
classified by documenting it as being focal or diffuse. A total of 68 subjects
with AGI were evaluated by 266 PET/CTs. A total of 36 examinations were
performed after the stop of antimicrobial therapy. Results include "higher
C-reactive protein (CRP) (adjusted coefficient per log10 mg/L 0.05 [95% C.I.
0.02-0.08]) was associated with higher SUVmax. CRP, metabolic and clinical
findings informed the decision to either start (medians of SUVmax 7.1 and CRP
31.5 mg/L; 100% focal uptake), escalate (SUVmax 9.5; CRP 31.5; 100% focal
uptake), continue (SUVmax 6.0; CRP 9.95 mg/L; 90% focal uptake), or stop
(SUVmax 4.3; CRP 3.5 mg/L; 61% focal uptake) antibiotic treatment. Of note,
decisions to escalate or continue antibiotic treatment were taken despite
normal CRP values in 12.5 and 35.7% of PET/CTs, respectively." Authors
conclude PET/CTs taken consecutively may influence decision-making patterns in
AGI patients.

Folmer et al. (2018) 57 performed a systematic review and meta-analysis to
determine diagnostic value of imaging techniques to diagnosis VGI. A total of
14 articles (eight prospective and six retrospective) were included. WBC
scintigraphy  SPECT/CT (I2 78.6%) demonstrated substantial heterogeneity. CTA
(I2 7.4%), 18F-PET (I2 36.5%), and 18F-PET/CT (I2 36.6%) yielded negligible to
moderate heterogeneity. Pooled sensitivity yielded 0.67 (95% CI 0.57-0.75) for
CTA, 0.94 (95% CI 0.88-0.98) 18F-PET of, 0.95 (95% CI 0.87-0.99) 18F-PET/CT,
0.90 (95% CI 0.85-0.94) WBC scintigraphy, and WBC scintigraphy with SPECT/CT
was 0.99 (95% CI 0.92-1.00). Pooled specificities were 0.63 (95% CI 0.48-0.76)
for CTA, 0.70 (95% CI 0.59-0.79) for 18F-PET, 0.80 (95% CI 0.69-0.89) for
18F-PET/CT, 0.88 (95% CI 0.81-1.94) for WBC scintigraphy, and WBC scintigraphy
SPECT/CT 0.82 (95% CI 0.57-0.96). Results demonstrated that WBC SPECT/CT
favors 18F-PET/CT when considering pre- and post-test results, yielding a
positive post-test probability of 96% versus 83%. Authors concluded that the
greatest method in diagnosing VGI results when diagnostic performance of WBC
scintigraphy is joined with SPECT/CT.

Ratliff et al. (2017) 58 performed a retrospective chart review study to
identify factors in patients that may increase the risk of vascular graft
infections (VGI) following abdominal or lower extremity revascularization
surgery. Electronic medical records were reviewed in patients who underwent
VGI or lower extremity revascularization surgery which included 28
preoperative, intraoperative, and post-operative factors. A total of 33 cases
of VGIs yielded an incidence rate of 15%. Preoperative factors were identified
with statistical significance for the development of VGI included sequential
procedures (p = .003), diabetes mellitus (p = .002), hemoglobin A1c greater
than 7.0 (p = .0002), blood glucose greater than 180 mg/dL (p = .0006), and
lack of mobility (0.0097). Associated VGI Intraoperative factors consisted of
hemostatic agents when applied to the surgical field intraoperatively (p =
.003) and perioperative hypoxemia (p = .027). Associated VGI postoperative
influences at discharge from the hospital to skilled nursing facility or acute
rehabilitation facility (p = .005) and unscheduled clinic visits (p = .008).
Authors concluded the results show vigilance is required to prevent VGI and
the importance of identifying associated risk factors.

Keidar and associates (2014) 59 retrospectively mined a database for cancer
patients with prosthetic vascular grafts. Data points included graft location,
material, and time from surgery. Two nuclear medicine physicians reviewed
imagines for consensus considering presence and patterns of increased 18F-FDG
uptake. A total of 107 prostheses (43 patients) were identified. Prostheses
materials consisted of Dacron (67), Gore-Tex (33) and 7 were native veins.
Diffuse homogeneous uptake was noted in 68 and inhomogeneous uptake in 30
grafts. A total of 9 grafts demonstrated no increased 18F-FDG uptake. Diffuse
18F-FDG uptake was found in 92% of noninfected vascular prostheses, with
Dacron grafts demonstrating more than with other materials. The degree of 18F
uptake remained the same over time. Authors concluded the information of 18F
uptake in noninfected vascular prostheses including presence, patterns and
persistence could increase the quality of interpretation of 18F-PET/CT studies
in suspected prosthetic infection patients.

The European Society for Vascular Surgery (ESVS) published clinical practice
guidelines on the management of Vascular graft and endograft infections in
2020.60 ESVS recommends "for patients with a clinical suspicion of vascular
graft/endograft infection and with non-convincing findings on CTA, the use of
18F- PET combined with low dose CT is recommended as an additional imaging
modality to improve diagnostic accuracy" offering a Class B recommendation
"Data derived from a single randomized clinical trials or large non-randomized
studies."

_Large-vessel Vasculitis_

__

Angelotti et al.61 (2021) retrospectively assessed 47 patients affected by
large-vessel vasculitis (LVV), evaluating clinics, blood chemistry and 18F-PET
results to evaluate the utility of 18-FDG, compared with traditional
assessments, in the short- (average 8 months after diagnosis) and long-term
(average 29 months). follow-up. Patterns of vascular involvement in patients
with Takayasu's arteritis (TAK) and giant cell arteritis (GCA) were compared.
Disease activity was assessed by clinical condition and inflammation markers
were evaluated at two time points. A significant decrease in the mean value of
SUV max in 18F-PET uptake was reported during follow-up in all patients. When
comparing 18F-PET uptake and target-to-background ratio (TBR) between short
and longer term follow up, the radiologist determined 38 positive 18F-PETs at
short-term evaluation. Fifteen remained positive, 23 turned out to be negative
and one that was previously negative turned positive. The mean value of SUV
max at short term follow-up was 4.09 (SD2.13) with long-term follow-up of
2.23 (SD1.13) in all patients. In all patients 18FDG PET uptake decreased
significantly (p<0.001) during follow-up. All TBR districts analyzed changed
significantly (p<0.001) when comparing short- and long-term durations. Authors
concluded that results establish 18F-PET as a useful tool in the evaluation of
LVV, at diagnosis and monitoring phases of disease. They further state study
data confirms that GCA and TAK are part of the same disease range.

Quinn et al (2020) conducted a prospective, observational cohort study to
determine the impact of imaging acquisition time on interpretation of disease
activity on 18F-PET in large-vessel vasculitis (LVV). A total of 79 patients
(GCA=44, TAK=35) were assessed and provided 168 paired one- and two-hour PET
studies resulting in 56% (94/168) scans were interpreted as active at the one-
hour time point, and 77% (129 scans) were interpreted as active at the two-
hour time point (p< 0.01). Results show that patients in the Dual active group
(OR 1.71, 95%CI 1.06-2.93; p =0.04) and the delayed group were significantly
more likely to have clinically active disease (Odds Ratio 1.94, 95%CI
1.13-3.53; p=0.02) when compared to the to the dual inactive group. Authors
concluded a large sum of LVV patients were detected as active when delayed
imaging was executed.

Lee et al. (2019)62 conducted systematic review and meta-analysis to evaluate
the performance of 18F-PET or 18F-PET/CT in the assessment of disease activity
in patients with LVV. Nine studies comprised of 439 18F-PET images from 298
patients resulted in a sensitivity of 0.88 [95% confidence interval (CI)
0.79-0.93] without heterogeneity (2 = 14.42, P = .07) and a pooled
specificity of 0.81 (95% CI 0.64-0.91) with heterogeneity (2= 63.72, P = .00)
for the detection of active LVV. The pooled DOR was 30 (95% CI 8-107).
Hierarchical sROC curve indicates that the area under the curve was 0.91 (95%
CI 0.89-0.94) suggesting good performance for the detection of active disease.
Authors concluded the detection of active disease status in patients with LVV
was achieved by performing 18F-PET or 18F-PET/CT. Further assessments should
be conducted to determine the impact on outcomes of 18F-PET imaging in LVV
patients.

A 2018 joint procedural recommendation by European Association of Nuclear
Medicine (EANM), Society of Nuclear Medicine and Molecular Imaging (SNMMI),
and the PET Interest Group (PIG), and endorsed by the American Society of
Nuclear Cardiology (ASNC) 63 regarding 18F-PET/CT(A) imaging in large vessel
vasculitis and polymyalgia rheumatica was published. In regard to management
of patients with suspected LVV and 18F-PET, a consensus was reached that
states "Based on the available evidence, 18F-PET imaging exhibits high
diagnostic performance for the detection of LVV and PMR (evidence level II,
grade B)." They go on to state "further studies are needed to select the most
clinically relevant and reproducible criteria for defining the presence of LVV
with 18F-PET, as well as to test the clinical impact of 18F-PET imaging on the
management of patients with suspected LVV."

Grayson et al.64 (2018) performed a prospective, longitudinal study with a
cohort of patients with large vessel vasculitis to evaluate the clinical value
of 18F-PET in a prospective cohort of patients with large-vessel vasculitis
(LVV) and disease comparators. A total of 115 subjects (LVV=56;
comparators=59) provided 170 18F-PET scans. Clinically active LVV and disease
comparators were differentiated utilizing 18F-PET with a sensitivity=85%
(95%CI: 69-94%) and specificity=83% (95% CI: 71-91%). A result of 58% (41/71)
were classified as active vasculitis in LVV patients in clinical remission. In
clinical remission patients who underwent 18F-PET it was determined that
future relapse was more common in elevated PETVAS scores (45% versus 11%,
p=0.03) over 15 months. Authors concluded that 18F-PET was beneficial in the
assessment of LVV aside from clinical assessment alone and future clinical
relapse was associated with 18F-PET scan activity during clinical remission.

Barra and associates65 (2018) performed a systematic review and meta-analysis
to determine the effectiveness of imaging modalities for the management of
Takayasu's Arteritis (TAK). A total of 57 studies were included with most
lacking robust design, quality and adequate sample size. In regard to TAK
diagnosis, ultrasound (US) demonstrated a lower pooled sensitivity of 81% (95%
CI: 69-89%) when compared to Magnetic Resonance Angiography (MRA) with
sensitivity (SN) 92% (95% CI: 88-95%), and US and MRA yielded specificities
(SP) >90%. Computed tomography angiography (CTA) resulted in a SN and a SP for
TAK diagnosis of >90%. Disease prediction varied across studies when
considering the utility of vessel wall thickening and enhancement by MRA and
CTA. Pooled results for disease activity utilizing 18F-PET were SN of 81% (95%
CI: 69-89%) and SP of 74% (95% CI: 55-86%). Authors concluded although US, CTA
and MRA are effective in the diagnosis of TAK, the utility remains uncertain
when considering assessing disease activity.

Puppo et al.66 (2014) executed a systematic review to assess the various
qualitative and semiquantitative methods for diagnosis and grading of vascular
inflammation in giant cell arteritis (GCA) patients (with or without
associated polymyalgia rheumatica (PMR)) utilizing 18F-PET. TAK was excluded
from analysis. A total of 19 articles (13 prospective and 6 retrospective)
were included resulting in a total of 442 patients (with or without PMR
symptoms) and 535 controls. Vascular inflammation was assessed in GCA in 10
studies that used qualitative 18F uptake criteria, 6 used semiquantitative
criteria, and 3 utilized qualitative and semiquantitative criteria. Diagnostic
GCA-related vascular inflammation utilizing 18F-PET scans to determine
severity based on diagnostic performance and examining their respective
advantages and limitations. Authors concluded most studies reviewed used the
qualitative methods of 18F-PET image assessment. Whereas the aortic to blood
pool uptake ration for the aortic arch proved to be more accurate among
semiquantitative approaches.

_Cardiac Amyloidosis_

__

The ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI published a 2 part expert consensus
recommendations for multimodality imaging in cardiac amyloidosis: evidence
base and standardized methods of imaging in which states while molecular
imaging techniques show promise, limited data is available therefore further
studies are needed for F-labelled PET tracers to detect early amyloidosis.
67,68

__

_Joint Arthroplasty_

__

Periprosthetic joint infection (PJI) occurs in around 0.5 to 1.0 percent of
hip arthroplasties. This percentage is expected to rise due to an aging
population. The occurrence of PJI can lead to significant quality of life
impairment, including chronic infection until loss of limb or amputation.69

UpToDate states "positron emission tomography (PET) scans, computed tomography
(CT) scans, magnetic resonance imaging (MRI) scans, or bone scans are not
useful for routine diagnostic evaluation in most cases of suspected prosthetic
joint infection (PJI)." False positives have also been presented when
18F-PET/CT was conducted in the first year of arthroplasty. When PJI was
predetermined, the accuracy of 18F-PET was higher in THA infection.69

The American College of Radiology (ACR)70 constructed an appropriateness
criterion for imaging following total hip arthroplasty. In-111 WBC and Tc-99m
sulfur colloid scan hip was often considered the best imaging test for
evaluating patients with a painful primary total hip arthroplasty where
infection was not excluded. They include 18F-PET hip as "may be
appropriate".71

The American Academy of Orthopaedic Surgeons (AAOS) produced Evidence-Based
Clinical Practice Guideline on the Diagnosis and Prevention of Periprosthetic
Joint Infections.72 Limited strength evidence supports the use of 18F-PET/CT,
18F-NaF and CT to aid in the diagnosis of PJI. Strength of Recommendation:
Limited - "Description: Evidence from two or more "Low" quality studies with
consistent findings or evidence from a single "Moderate" quality study
recommending for or against the intervention or diagnostic test or the
evidence is insufficient or conflicting and does not allow a recommendation
for or against the intervention." 72

A consensus document was produced by the European Association of Nuclear
Medicine (EANM), European Society of Radiology (ESR), European Bone and Joint
Infection Society (EBJIS), and with European Society of Clinical Microbiology
and Infectious Diseases (ESCMID) endorsement.73 A consensus was reached that
18F-PET in patients with suspected prosthetic joint infection demonstrated a
high sensitivity but lower specificity when compared to white blood cell
scintigraphy or anti-granulocyte antibody scintigraphy with a level of
evidence: 2.

Jin and colleagues74 (2014) conducted a systematic review and meta-analysis of
published literature on the diagnosis of prosthetic infection after
arthroplasty. Fourteen studies with 838 prostheses with suspicious of
prosthetic infection after arthroplasty were included in the meta-analysis. "A
pooled sensitivity of 18F-PET or 18F-PET/CT in detecting prosthetic infection
was 86% (95% confidence interval [CI] 82-90%) on a per prosthesis-based
analysis. The pooled specificity of 18F-PET or 18F-PET/CT in detecting
prosthetic infection was 86% (95% CI 83-89%) on a per prosthesis-based
analysis. The area under the ROC curve on a per prosthesis-based analysis was
0.93." Authors concluded that patients suspicious of prosthetic infection,
18F-PET or 18F-PET/CT demonstrated high sensitivity and specificity but report
possible sources of false positive results. Limitations included statistically
heterogeneous studies, inclusion of studies with limited power, moderate
quality, and small sample sizes. The authors report no conflicts of interest.

Authors van der Bruggen et al.75 (2010) conducted a systematic review.
PubMed/MEDLINE and Embase were searched for publications on SPECT and 18F-PET
on osteomyelitis and prosthetic bone and joint infections. The search produced
44 articles (15 for SPECT and 29 for 18F-PET comprised of 1634 patients (580
patients SPECT, 1054 patients 18F-PET). In 18F-PET performance in orthopedic
implant infections, sensitivity varies widely from 28% to 91% and specificity
from 9% to 97%. The highest diagnostic accuracy of for diagnosis of bone and
joint infections is achieved with combined 111In-WBC and 99mTc-sulfur colloid
for SPECT was reported as 95%. Authors concluded SPECT/computed tomography
(CT) with 111In-WBC combined with 99mTc-MDP or 99mTc-sulfur colloid is the
ideal imaging technique for diagnosis of bone and joint infections. While
18F-PET is useful for diagnosis of osteomyelitis which enables more accurate
localization with improved spatial resolution over SPECT imaging. Adding CT
further improves localization. Limitations include small sample sizes, low and
moderate levels of evidence in included studies, with a wide range inclusion
criterion and outcomes. The authors report no conflicts of interest.

Mushtaq76 and associates (2019) performed a review on radiological imaging
modalities in the evaluation of the failing total hip arthroplasty. Despite
18F-PET enabling visualization of inflammatory cells during infection, authors
state published results to date are inconclusive and have contradictory
findings.

Kumar and colleagues (2016)77 conducted a prospective study to evaluate 57 hip
components in 45 patients (bilateral prostheses in 12 patients, 45 painful and
12 asymptomatic contralateral hip components) with dual phase 18F-PET/CT
(DPFP) and three-phase bone scan (TPBS). The aim was to establish the clinical
utility of dual phase 18F-PET/CT in preoperative diagnosis of implant
loosening, differentiation between septic and aseptic loosening and to compare
the diagnostic accuracy of DPFP and TPBS. Two expert nuclear medicine
physicians were blinded (clinical findings and final diagnosis) evaluated
skeletal scintigraphy and 18F-PET/CT findings. Authors concluded that
18F-PET/CT is a useful modality for diagnosing septic loosening of hip
prostheses. Diagnostic DPRP imaging (early and delayed) demonstrated potential
to differentiate septic and aseptic loosening and over TPBS. Limitations
include small sample size, and lack of histopathology and microbiological
confirmation on asymptomatic stable joints. One patient experienced a high
tracer uptake resulting in the 18F-PET/CT being unable to differentiate
metastatic deposit from septic loosening. Authors report no conflicts of
interest.

Basu et al. (2014) performed a prospective study to assess and compare the
value of 18F-PET to combined 111In-labeled leukocyte/99mTc-sulfur colloid bone
marrow (WBC/BM) imaging for diagnosing infection in hip and knee prostheses.78
Suspected infected or noninfectious loosening of 221 prostheses (134 hip and
87 knee) were evaluated. WBC/BM imaging and 18F-PET was performed in 88
prostheses and 18F-PET was performed on all 221 prostheses. The evaluation of
hip arthroplasty using 18F-PET yielded a sensitivity, specificity, PPV, NPV,
and AUC were 81.8%, 93.1%, 79.4%, 94.0%, and 0.874, respectively. The
evaluation of hip arthroplasty using WBC/BM imaging yielded a sensitivity,
specificity, PPV, NPV, and AUC of 38.5%, 95.7%, 71.4%, 84.6%, and 0.671,
respectively. There was no significant difference in sensitivity (P=0.0625) or
specificity (P=1.000) in those cases that underwent both 18F-PET and WBC/BM
imaging modalities. The evaluation of knee arthroplasty using 18F-PET yielded
a sensitivity, specificity, PPV, NPV, and AUC were 94.7%, 88.2%, 69.2%, 98.4%,
and 0.915, respectively. The evaluation of knee arthroplasty using WBC/BM
imaging yielded a sensitivity, specificity, PPV, NPV, and AUC were 33.3%,
88.5%, 25.0%, 92.0%, and 0.609, respectively. Cases that underwent both
18F-PET and WBC/BM imaging yielded no significant differences in sensitivity
and specificity (P=0.500 and P=1.000, respectively). Authors conclude use of
18F-PET scan in detecting infection in painful hip and knee prostheses is
optimal based on diagnostic performance in this study and when considering the
cost and safety issues associated with WBD/BM imaging. Limitations include a
limited number of patients had both studies, not all patients with knee
arthroplasty were assessed with both imaging modalities. This study made use
of standalone 18F-PET rather than 18F-PET/CT which is more commonly used.

Koob et al. (2019) conducted a retrospective analysis to assess the
sensitivity and specificity in diagnosing periprosthetic loosening in total
hip and knee arthroplasty utilizing 18F-Fluoride 18F-PET/CT in 26 patients.79
A sensitivity of 95.00%, a specificity of 87.04% and an accuracy of 89.19% for
18F- PET/CT. Authors conclude 18F-PET/CT is helpful in diagnosing
periprosthetic loosening of total hip and knee arthroplasties, further
investigation is needed with larger sample sizes and more focus on uptake
kinetics to assess 18F-PET/CT in periprosthetic joint infection to establish
its value in distinguishing aseptic from septic loosening. Authors report no
conflicts of interest.

SMEs discussed there is a limited role in evaluation of arthroplasty and that
laboratory analysis and aspiration of joint with cultures is standard
evaluation. This indication is challenged by lower quality and greater
variability in the evidence but feels there is a role in complicated cases.
They also discussed the potential to replace the current 3-phase bone scan
which is time-consuming, labor-intensive approach that also delays results and
could potentially simplify management. There is also lack of clarity within
the literature on the duration of time after surgery to obtain the most
accurate results with 1-2 years being discussed from literature sources.

_Chronic Osteomyelitis_

__

Osteomyelitis is an infection involving the bone and may be classified based
on mechanism of infection (hematogenous versus nonhematogenous) and illness
duration. Diagnosis of osteomyelitis is established via culture obtained from
biopsy of the involved bone and should be performed before antibiotic therapy
is initiated.80 Radiographic imaging can be helpful in the diagnosis,
delineating the extent of disease, and planning therapy in patients with
osteomyelitis. Magnetic resonance imaging (MRI) is the imaging modality with
greatest sensitivity and a negative predictive value for diagnosis of
osteomyelitis. An alternative test may include 18F-PET, computed tomography
(CT), tagged white blood cell (WBC) or three-phase bone scan plus/minus, or
single photon emission CT (SPECT-CT) in cases where MRI is not feasible.81

SMEs discussed there are multiple entities to consider including acute vs.
chronic osteomyelitis, diabetic foot and other locations to consider, but
there is overall a lack of high-quality evidence for the role of 18F-PET scan.
Current standard for diagnosis of osteomyelitis is MRI and some studies
suggest 18F-PET may have similar sensitivity. For diabetic foot consideration
of blood sugar control must be made as this is important to get an accurate
18F-PET scan. Also, diagnosis typically requires biopsy and while imaging may
guide determining the location for biopsy it will not typically replace biopsy
which is necessary to confirm the diagnosis and for cultures. Once advantage
to 18F-PET scan is the whole-body scan to understand extent of disease. This
may also impact staging of disease and decision making.

A consensus document82 for the diagnosis of peripheral bone infection in
adults by European Bone and Joint Infection Society, European Society of
Microbiology and Infectious Diseases, European Society or Radiology, and
European Association of Nuclear Medicine state the gold standard for diagnosis
of bone infection is bone biopsy and culture of affected bone. This should be
performed under image guidance typically CT guidance however X-ray of
fluoroscopy may be utilized. MRI has a high diagnostic performed radiation
with minimal radiation exposure and wide availability. 18F-PET/CT has high
sensitivity and specificity implants or recent surgery or fractures, but also
has higher radiation exposure. The panel states Level of Evidence 2 for
18F-PET/CT as having high diagnostic accuracy in peripheral bone infection
without fracture and osteosynthesis. The panel did agree there is not
sufficient evidence for use of this modality as the current reference standard
and is typically performed in chronic osteomyelitis to the role in acute phase
is still unknown. Comparative studies to WBS scintigraphy are too small to be
definitive.

Wang et al conducted a meta-analysis including 23 studies on 851 patients
evaluating the role of **** 18F-PET, three-phase bone scintigraphy, leukocyte
scintigraphy, and MOAB scintigraphy in the assessment of suspected
osteomyelitis. They report that 18F-PET had a pooled sensitivity of 0.923,
specificity of 0.920, and AUC of 0.9666, whereas for bone scintigraphy, the
corresponding values were 0.827, 0.446, and 0.6514. The authors conclude
18F-PET is superior to other radionucleotide imaging modalities for the
detection of chronic osteomyelitis.83

Kulkarni and colleagues (2020) conducted a retrospective analysis to evaluate
the diagnostic performance of 18F-PET/CT in patients with skull base
osteomyelitis (SBO) compared to magnetic resonance imaging (MRI) whenever
available. Seventy-seven patients with suspected skull base osteomyelitis
(SBO) who underwent regional 18F-PET/CT were included in the review. Images
were analyzed for 18F uptake. Diagnostic performance of 18F-PET/CT was
analyzed based on histopathology, culture, and clinical/imaging follow-up.
Fifty-six patients underwent both 18F-PET/CT and MRI. Agreement analysis
between the modalities yielded agreement for delineation of soft tissue and
bony involvement with K values of 0.82 and 0.81, respectively. Authors
concluded 18F-PET/CT was a sensitive tool in evaluation of patients with SBO.
18F-PET/CT shows a good agreement with the MRI. This study is limited by the
retrospective study design, potential selection bias and a lack of
histopathology across the study population.84

Recommendations for the treatment of osteomyelitis (2014) were published after
a multi-professional team conducted a literature review. The aim was to
produce a guided medical approach to different types of osteomyelitis, aiming
to obtain better clinical outcomes and reducing the social costs of this
disease. A multidisciplinary approach while considering palliative treatment
and a curative approach is important in the assessment of each case. Treatment
for chronic osteomyelitis include "correct microbiological diagnosis;
improvement of the host's defenses; stabilization of underlying diseases;
correct anatomical localization of bone involvement; adequate antimicrobial
therapy; surgical debridement of all devitalized tissue; repair of soft
tissues; and bone reconstruction and rehabilitation." 85

Termaat et al. (2005) conducted a systematic review and meta-analysis to
determine the accuracy of current imaging modalities in the diagnosis of
chronic osteomyelitis. Each imaging technique was evaluated by determining its
sensitivity and specificity compared with the results of histological
analysis, findings on culture, and clinical follow-up of more than six
months.86 Twenty-three clinical studies included accuracy information for
radiography (2 studies), magnetic resonance imaging (5), computed tomography
(1), bone scintigraphy (7), leukocyte scintigraphy (13), gallium scintigraphy
(1e), combined bone and leukocyte scintigraphy (6), combined bone and gallium
scintigraphy (3), and fluorodeoxyglucose positron emission tomography (4) and
were included in the review. Pooled sensitivity established that 18F-PET was
the most sensitive technique, with a sensitivity of 96% (95% confidence
interval, 88% to 99%) compared with 82% (95% confidence interval, 70% to 89%)
for bone scintigraphy, 61% (95% confidence interval, 43% to 76%) for leukocyte
scintigraphy, 78% (95% confidence interval, 72% to 83%) for combined bone and
leukocyte scintigraphy, and 84% (95% confidence interval, 69% to 92%) for
magnetic resonance imaging. Pooled specificity established that bone
scintigraphy had the lowest specificity, with a specificity of 25% (95%
confidence interval, 16% to 36%) compared with 60% (95% confidence interval,
38% to 78%) for magnetic resonance imaging, 77% (95% confidence interval, 63%
to 87%) for leukocyte scintigraphy, 84% (95% confidence interval, 75% to 90%)
for combined bone and leukocyte scintigraphy, and 91% (95% confidence
interval, 81% to 95%) for PET scan. The sensitivity of leukocyte scintigraphy
in detecting chronic osteomyelitis in the peripheral skeleton was 84% (95%
confidence interval, 72% to 91%) compared with 21% (95% confidence interval,
11% to 38%) for its detection of chronic osteomyelitis in the axial skeleton.
The specificity of leukocyte scintigraphy in the axial skeleton was 60% (95%
confidence interval, 39% to 78%) compared with 80% (95% confidence interval,
61% to 91%) for the peripheral skeleton. Authors concluded 18F-PET exhibited
the highest diagnostic accuracy for confirming or excluding the diagnosis of
chronic osteomyelitis. While leukocyte scintigraphy demonstrated an
appropriate diagnostic accuracy in the peripheral skeleton, 18F-PET was
superior for detecting chronic osteomyelitis in the axial skeleton. This
analysis was limited by the overall low quality of the evidence with the
author rating the level of evidence as III due to multiple factors including
non-consecutive studies, studies without consistently applied reference
standards, lack of blinding, small sample sizes and other factors.

__

_Diabetic Foot_

Llewellyn and associates (2020) published a systematic review and meta-
analysis to review the evidence on the diagnostic accuracy of imaging tests to
diagnose osteomyelitis in people with diabetic foot ulcers.87 36 studies were
evaluated and reported the sensitivities of MRI (96.4%), PET scans (84.3%),
SPECT (95.6% but only based on 3 studies), scintigraphy (84.2%), and X- rays
(61.9%). The authors conclude that MRI and PET scan both reliably diagnosed
osteomyelitis and diabetic foot ulcer patients with Maria being the current
preferable test given its wider availability and lack of potential harmful
radiation.

Lauri et al.88 (2020) conducted a retrospective multicenter study to compare
the diagnostic accuracy of white blood cell scintigraphy (WBC), 18F-PET/CT,
and Magnetic Resonance Imaging (MRI) in patients with suspected diabetic food
infection (DFI). A total of 251 patients from five centers were enrolled and
clinical and imaging data was reviewed. Sensitivity, specificity and accuracy
of WBC, FDG, and MRI for diagnosing osteomyelitis (OM), soft-tissue infection
(STI), and Charcot osteoarthropathy. Median values of CRP and ESR were
significantly higher in OM patients when compared to patients without
infection (p = 0.017 and p = 0.027 respectively) in a post hoc analysis. In
patients with STI and normal subjects and between patients with OM and STI, no
significant difference was observed. When information on the pathogen casing
the infection could not be obtained, biopsy was used as the gold standard for
final diagnosis in those 36 patients. A total of 67 subjects underwent skin
cultures and 14 of 50 subjects underwent pre- or intra-operative biopsies
resulting in causative pathogens being recorded. Clinical follow up was
utilized in the remaining 121 subjects to establish a final diagnosis. Results
included OM (n=93), STI (n=76), and Charcot (n=10). No pathology was required
in 72 subjects according to reference standard. Imagining modalities resulted
in WBC scintigraphy (n=119), 18F-PET/CT (n=46), and MRI (n=59). WBC and
18F-PET/CT were performed in 10 subjects, WBC scintigraphy and MRI were
performed in 15 subjects, and all three imaging modalities were performed in 2
subjects. When considering STI, FDG and WBC reached a significantly higher
specificity than MRI (97.9% and 95.7% vs. 83.6%, p = 0.04 and p = 0.018,
respectively). In Charcot, WBC was more specific than MRI (89.3% vs. 88.2% p <
0.0001) and MRI and WBC were significantly higher specificity and accuracy
than FDG (88.2% and 89.3% vs. 62.5%, p = 0.0009; 80.3% and 87.9% vs. 62.1%, p
< 0.02, respectively). When considering WBC in patients with suspected DFI,
the utilization of EANM guidelines resulted in the most reliable imaging
modality to differentiate between OM, STI, and Charcot. Authors concluded the
study results confirm WBC scintigraphy is the superior imaging modality when
delineating pedal OM, STI, and Charcot. Examinations results include high
sensitivity, specificity, and accuracy when European Society of Nuclear
Medicine (EANM) guidelines are applied. Authors recognize the need for
additional research with more robust study designs.

The same author conducted a 2017 systematic review and meta-analysis on 27
articles evaluating compared the diagnostic performances of MRI, radiolabeled
white blood cell (WBC) scintigraphy (either with 99mTc-
hexamethylpropyleneamineoxime [HMPAO] or 111In-oxine), and 18F-PET in
diagnosis of diabetic foot infections.89 The authors report the sensitivity of
18F-PET/CT as 89%, 111In-oxine as 92%, WBC scan as 91% and MRI as 93%.
Specificities were 92%, 75%, 92% and 75% respectively. They conclude that the
18F-PET/CT and WBC scan offered highest specificity but larger prospective
studies with direct comparison among the imaging techniques are required. This
study was limited by the number of published articles, variability in
technique, small number of patients in most studies, risk of biased and
variability and diagnostic criteria of osteomyelitis

Diez et al. (2020) performed a prospective study to compare the diagnostic
accuracy of diffusion-weighted imaging (DWI) and dynamic contrast-enhanced-
magnetic resonance imaging (DCE-MRI) involving two region of interest (ROI)
sizes with 18F-PET/CT to differentiate diabetic foot osteomyelitis (DFO) from
Charcot neuro-osteoarthropathy (CN). Thirty-one diabetic patients were
included. Two readers independently evaluated DWI and DCE-MRI parameters using
two different ROI sizes, and 18F-PET/CT parameters (visual assessment, SUVmax,
delayed SUVmax, and percentage changes between SUVmax and delayed SUVmax).
Authors concluded DWIr, Ktrans and iAUC60 allowed reliable differentiation of
DFO and CN. The 18F-PET/CT was the most accurate technique for differentiation
in visual assessment. 90

Kagna and associates (2012) conducted a prospective study assess the value of
18F-PET/CT in diabetic patients with clinically suspected osteomyelitis. A
total of 39 consecutive diabetic patients were enrolled. 18F-PET/CT was
evaluated, and final diagnosis was founded on histopathology and bacteriology
of surgical samples, or clinical and imaging follow-up yielding in 18
confirmed cases of osteomyelitis and exclusion of 21 sites. Twenty lesions
with focal bone FDG uptake, yielded 2 that were false-positive with no further
evidence of osteomyelitis. Diffuse FDG uptake involving more than one bone on
CT were correctly diagnosed as diabetic osteoarthropathy in 5 sites. Results
of 18F-PET/CT yielded a sensitivity, specificity, and accuracy of 100%, 92%
and 95% in a patient-based analysis and 100%, 93% and 96% in a lesion-based
analysis, respectively, for the diagnosis of osteomyelitis in the diabetic
foot. Authors concluded "18F-PET/CT was found to have high performance indices
for evaluation of the diabetic foot. The PET component identified FDG-avid
foci in sites of acute infection which were precisely localized on fused
18F-PET/CT images allowing correct differentiation between osteomyelitis and
soft-tissue infection." 91

Schwegler et al. (2008) performed a prospective study in 20 diabetic patients
with a chronic foot ulcer (>8 weeks) without antibiotic pretreatment and
without clinical signs for osteomyelitis. With the purpose of assessing the
prevalence of clinically unsuspected osteomyelitis and to compare the value of
magnetic resonance imaging (MRI), 18F-PET and 99mTc-labelled monoclonal anti
granulocyte antibody scintigraphy (99mTc-MOAB). Bone biopsy confirmed presence
of osteomyelitis in seven of the 20 clinically unsuspected foot ulcers. MRI
was positive in six of the seven patients with proven osteomyelitis, whereas
18F-PET and 99mTc-MOAB were positive only in (the same) two patients. Authors
conclude that MRI appears to be superior to 18F-PET and 99mTc-MOAB in
detecting foot ulcer-associated osteomyelitis. 92

_Spondylodiscitis (SD)_

Guidance was published by the Society of Nuclear Medicine and Molecular
Imaging and the American College of Nuclear Medicine (SNMMI) to describe
appropriate use of nuclear medicine imaging in patients suspected of having
various musculoskeletal infections. (Palestro, Clark et al. 2021) Appropriate
use was based on expert panel consensus and evidence review from existing
systematic reviews. In all the scenarios reviewed below evidence was rated
fair unless there was no evidence to review.

  * Diagnosis of spondylodiscitis in patients without spinal hardware, 18F-PET/PET-CT (Score 9 - Appropriate) based on fair evidence and expert opinion.
  * Diagnosis of spondylodiscitis in patients with spinal hardware, 18F-PET/PET-CT (Score 8 - Appropriate)- based on fair evidence and there were higher false positive rates in the present of spinal hardware than without (12.8% vs. 7%) based on fair evidence and expert opinion.
  * Diagnosis of uncomplicated peripheral bone osteomyelitis, 18F-PET/PET-CT (Score 9 - Appropriate) based on fair evidence (from 2 SRs) and expert opinion.
  * Diagnosis of complicated peripheral bone osteomyelitis, including orthopedic hardware infection, 18F-PET/PETCT (Score 8 - Appropriate).
  * Diagnosis of foot osteomyelitis in diabetic patients, 18F-PET/PET-CT (Score 8 - Appropriate)
  * Diagnosis of PJI of the hip, 18F-PET/PET-CT (Score 7 - Appropriate)
  * Diagnosis of PJI of the knee, 18F-PET/PET-CT (Score 6 - May be Appropriate)
  * Diagnosis of PJI of the shoulder, 18F-PET/PET-CT (Score 5 - May be Appropriate)- no evidence to review.
  * Diagnosis of septic arthritis, 18F-PET/PET-CT (Score 6 - May be Appropriate)- no evidence to review.

A joint consensus document was published by EANM/ESNR and ESCMID-endorsed for
the diagnosis of spine infection (spondylodiscitis) in adults. 92

  * In primary and post-surgical SD, if MRI is contraindicated, the imaging modality of choice is 18F-PET/CT Level of evidence: 2.
  * In post-surgical SD, with or without spinal hardware, 18F-PET/CT can detect both spine infection and soft tissue infection Level of evidence: 2.
  * In patients with suspected spine infection and elevated ESR and/or CRP and doubtful MRI, 18F-PET/CT should be performed Level of evidence: 1.
  * In patients with suspected spine infection, elevated ESR and/or CRP, doubtful or unperformable MRI, and doubtful or unperformable 18F-PET/CT, a CT scan should be performed with an image-guided biopsy. Level of evidence: 2
  * The role of hybrid PET/MRI, although promising, needs to be evaluated. Level of evidence: 5
  * In case of negative MRI or negative 18F-PET/CT, the diagnosis of SD should be excluded. Level of evidence: 5
  * In patients with SD diagnosed by 18F-PET/CT, a second 18F-PET/CT scan can be performed to evaluate the response to antibiotic therapy. Level of evidence: 4

Corticosteroid, antiepileptics, catecholamines and chemotherapy (within 1
month of end of therapy) can alter the qualitative analysis of 18F-PET and
must be considered for patient selection.93 While sensitivity and negative
predictive value is high for 18F-PET/CT it may be reduced by presence of
tumor, degenerative spinal disease and/or spinal implants. In one small
prospective study MRI was superior for abscess detection while 18-PET/CT was
better for metastatic infection.94,95  
  
  

_Fever of Unknown Origin (FUO)_

Initial studies on 18F-PET scan utilization for detection of fever of unknown
origin are retrospective and there was not sufficient evidence for development
of appropriate use criteria. Additional prospective studies have helped to
identify a subset of populations who may benefit from the utilization of this
technology. Using a clear definition of fever of unknown origin, consistent
with that used in these prospective studies, the range of performance for
18F-PET/CT for FUO reports sensitivities ranging from 52-85% and diagnostic
yield  50%. 18F-PET/CT appears to be superior to other nuclear imaging
methods such as 18F-PET without CT, or gallium or leukocyte scintigram,
although there are no RCT to determine this definitively. Significantly, a
negative study correlates with a higher rate of spontaneous remission which
clinically allows providers to feel more confident in an observation approach
in these cases. CGS Administrators considers the use of 18F-PET/CT reasonable
and medically necessary in this limited population, however broader use of
this technology for detection of fever as defined in this policy under
"Covered Indications" not been established by the literature and will not be
considered reasonable and necessary.

_Cardiac_

Most cases of infective endocarditis can be diagnosed the Modified Duke
Criteria as the current standard for diagnosis. 35 In rare cases when clinical
suspicion is high, but evaluation is inconclusive 18F-PET/CT has been shown be
a reasonable adjunctive in cases suspicion of endocarditis on a prosthetic
valve. Another advantage of 18F-PET/CT is the ability to detect extracardiac
disease which is not uncommon in this setting. This is supported by societal
guidance 10,35 and SME input. In the time period after valve replacement
18F-PET scan may not be able to distinguish post-operative changes from
infectious changes and other test such as WBC scan is preferred although the
precise timing after surgery has not been well-defined in the literature. The
sensitivity for 18F-PET/CT is much lower for native values with sensitives
consistently below 50% in multiple studies. Due to much lower sensitivity and
lack of a defined role for evaluation in native valve 18F-PET/CT is considered
investigational in this population.

Unlike endocarditis where there is an established diagnostic criterion (DC)
there is challenges in diagnosis of cardiac sarcoidosis (CS) which typically
relies on biopsy, but biopsy can also be inconclusive. High resolution CT scan
is considered first line imaging to distinguish sarcoidosis from the
interstitial lung followed by cardiac MRI.95 18F-PET/CT can detect FDG uptake
in the granulomatous cells producing inflammation with a fairly distinct
pattern so can inform on inflammatory processes not detected by other image
modalities. Use of a cardiac protocol to reduce the physiological uptake of
FDG is essential for accuracy. 18F-PET/CT also can detect the response to
treatment indicated by decrease in inflammatory activity not detectable by
routine imaging and guide treatment decisions. While the literature shows
fairly good sensitivity for CS this is based on overall low-quality studies
and further investigation is needed. However, given the lack of other reliable
modalities and the potentially for rapid deterioration with this condition in
the setting where standard imaging is inconclusive this can provide valuable
input. Additionally, there is supportive literature for a role of 18F-PET/CT
in the monitoring for therapy in proven CS therefore limited coverage for use
in this setting is considered reasonable and necessary. 46,96

In equivocal cases when CTA or MRA is inconclusive for vascular
graft/endograft infection 18F-PET/CT has been shown to have sensitivity above
CTA or MRA. Both 18-PET/CT or WBC scan with SPECT/CT offers higher sensitivity
and specificity and may be useful in equivocal cases and is recommended in
this role in guidelines with Class B recommendation.60 In cases where
18-PET/CT may be less useful such as post-op or when adhesives used may impact
interpretation WBC scan with SPECT/CT may be preferred modality.

Studies have explored the role of 18F-PET for diagnosis and monitoring of
disease progression in patients with vasculitis, and while there is some
potential role given the high sensitivity and specificity understanding the
impact of anti-inflammatory treatment on the study results has yet to be
delineated. Studies are limited to small prospective and retrospective studies
and additional investigation is necessary to determine if 18F-PET may play a
role in these conditions.

_Bone and Joint_

The role of 18F-PET/CT for joint arthroplasty has yet to be established. The
literature is low quality, and the reported sensitives have wide range of
variability. There is also evidence other modalities are superior. 18F-PET/CT
may potentially simplify the current complicated three-phase imaging
modalities used in complex cases, however there is not sufficient evidence to
support this replacement at this time and lack of any studies to compare these
modalities and access if this is a suitable replacement. Therefore, the use of
18F-PET/CT for evaluation of joint arthroplasty is considered investigational.

The use of 18F-PET/CT for evaluation of osteomyelitis including the role for
evaluation of diabetic foot remains investigational. Most literature is low
quality and results are inconclusive. Meta-analysis suggest that 18F-PET/CT is
superior to other radionuclide imaging modalities for detection of
osteomyelitis, however there are many restrictions including implants, recent
surgery or fractures. Additionally, there is not literature to support
superiority of PET scan over MRI which has a high diagnostic accuracy for
osteomyelitis, widespread availability and has the ability to detect the
presence and the extent of associated soft tissue abnormalities such as
tumors, muscular involvement or abscess formation which may clinically mimic
infection of bone.82 Further investigation can determine if there is a role
for determining the extent of disease and staging, but this has not yet been
established. Additional investigation in terms of impact of elevated blood
sugars for evaluation of diabetic foot must also be determined.

The diagnosis of spondylodiscitis can be challenged due to nonspecific
clinical and laboratory test. The test of choice is MRI. Evidence is limited
to fair quality evidence for the role of 18F-PET. While some early studies
suggest sensitivity is superior to other nuclear imaging modalities there is a
lack of quality evidence, comparison studies and diagnostic standards to fully
understand the role in this condition. There are also many factors that may
negatively influence quality of study and standardized patient selection and
protocols are lacking, therefore remains investigational until further
research addresses these limitations.

While additional indications have been explored for the use of 18F-PET and
18F-PET/CT for inflammation and infection there was insufficient evidence to
support a role of this modality and this time.