A meta-analysis of the value of fluorodeoxyglucose-PET/PET-CT in the evaluation of fever of unknown origin

doi:10.1016/j.ejrad.2010.11.018

European Journal of Radiology

Volume 80, Issue 3, December 2011, Pages 834-844

https://doi.org/10.1016/j.ejrad.2010.11.018 Get rights and content

Abstract

Background and purpose

The diagnosis of patients with fever of unknown origin (FUO) remains a challenging medical problem for internal medicine. A reliable estimate of the diagnostic performance of FDG-PET and FDG-PET/CT in the assessment of FUO unidentified by conventional workup has never been systematically assessed, and present systematic review was aimed at this issue.

Methods

A systematic search for relevant studies was performed of the PubMed, Embase, and Cochrane databases. Methodological quality of each study was assessed. Sensitivity, specificity and area under the curve (AUC) were meta-analyzed. Subgroup analyses were performed if results of individual studies were heterogeneous.

Results

The inclusion criteria were met by nine studies. Overall, the studies had good methodological quality. Pooled sensitivity and specificity of FDG-PET for the detection of FUO 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. Heterogeneity among the results of FDG PET studies was present (QSE = 12.40, I² = 67.7%; QSp = 35.98, I² = 88.9%). Pooled sensitivity and specificity of FDG-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. We did not find any statistical differences in the AUC and Q* index between FDG-PET and FDG-PET/CT (Z = 0.566, p > 0.05).

Conclusions

Although the FDG-PET studies that we examined were heterogeneous, FDG-PET appears to be a sensitive and promising diagnostic tool for the detection of the causes of FUO. FDG-PET/CT should be considered among the first diagnostic tools for patients with FUO in whom conventional diagnostics have been unsuccessful.

Introduction

The diagnosis of patients with fever of unknown origin (FUO) remains a challenging medical problem for internal medicine. The timely identification and precise localization of the cause of FUO is critical for determining the use of further invasive diagnostic procedures and for the prompt initiation of the appropriate treatment, both of which have a significant impact on patient care [1]. Conventional anatomical imaging modalities, such as computerized tomography (CT), magnetic resonance imaging (MRI), and ultrasound, are used to detect focal infectious and inflammatory processes. However, due to the absence of substantial anatomical changes, some lesions cannot be effectively detected at an early stage using these modalities [2]. In addition, CT, MRI, and ultrasound usually provide information for only a limited part of the body, and total body CT or MRI is not widespread [3]. ¹⁸F-fluorodeoxyglucose-positron emission tomography (FDG-PET) is a non-invasive diagnostic technique used in nuclear medicine that allows the identification of both the localization and the number of foci in all parts of the body based on functional changes [4]. This type of medical technology has been successfully used to detect the causes of FUO. In particular, with the introduction of combined PET/CT into the clinic, the simultaneous acquisition of accurately aligned, whole-body anatomical and functional images has increased our ability to assess the presence and location of foci of FUO [1]. However, the studies that have examined the use of FDG-PET are based on relatively small sample sizes [4], [5], [6], [7], [8], [9], and the adequacy of FDG-PET and FDG-PET/CT for the detection of FUO has still not been established. Therefore, the purpose of this study was to perform a meta-analysis to examine the overall diagnostic performance of FDG-PET and FDG-PET/CT for the detection of FUO, which cannot be identified by conventional diagnostic methods.

Section snippets

Search strategy

We searched several electronic databases (PubMed, Embase, and Cochrane) for studies published between January 1990 and March 2010 using the following key words: “positron emission tomography” or “PET”; “positron emission tomography/computer tomography” or “PET/CT”; “fever of unknown origin,” “fever of undetermined origin,” or “FUO”; and “fluorodeoxyglucose” or “FDG.” No language restriction was applied to the search. Based on our results, we generated a bibliography of references that comprised

Literature review

Based on the computer search and on extensive cross-checking of the references, we extracted 96 abstracts for analysis; however, 66 articles were excluded on the basis of their abstracts. We then screened 30 articles in full text. The selection process and reasons for exclusion of the articles are summarized in Fig. 1. A total of nine studies representing 388 patients were eligible for inclusion in the meta-analysis, of which five were FDG-PET studies and four were FDG-PET/CT studies (Table 1).

Study description

Discussion

Because F-18 FDG, a glucose analog, accumulates not only in malignant tissues but also in sites of infection, inflammation, and autoimmunity [26], [27], FDG-PET may be a more suitable imaging modality than conventional anatomical imaging for the evaluation of FUO [25], [28]. To our knowledge, this meta-analysis is the first to use summary estimates to evaluate the accuracy of FDG-PET and FDG-PET/CT for the detection of FUO. We analyzed nine different studies that collectively evaluated 388

Financial support

We acknowledge grants from the Natural Science Foundation of China (No. 30870730), the Science and Technology Planning Project of Zhejiang Province (No. 2009C33109), and the Medical Scientific Research Foundation of Zhejiang Province (No. 2007A072).

Conflict of interest

The authors declare that there are no conflicts of interest.

References (46)

I. Buysschaert et al.
Contribution of (18)fluoro-deoxyglucose positron emission tomography to the work-up of patients with fever of unknown origin
Eur J Intern Med
(2004)
J. Ferda et al.
Fever of unknown origin: a value of (18)F-FDG-PET/CT with integrated full diagnostic isotropic CT imaging
Eur J Radiol
(2010)
J.B. Reitsma et al.
Bivariate analysis of sensitivity and specificity produces informative summary measures in diagnostic reviews
J Clin Epidemiol
(2005)
S. Vanderschueren et al.
Inflammation of unknown origin versus fever of unknown origin: two of a kind
Eur J Intern Med
(2009)
D. Blockmans et al.
Positron emission tomography in giant cell arteritis and polymyalgia rheumatica: evidence for inflammation of the aortic arch
Am J Med
(2000)
M.F. Neurath et al.
Noninvasive assessment of Crohn's disease activity: a comparison of 18F-fluorodeoxyglucose positron emission tomography, hydromagnetic resonance imaging, and granulocyte scintigraphy with labeled antibodies
Am J Gastroenterol
(2002)
Z. Keidar et al.
Fever of unknown origin: the role of ¹⁸F-FDG PET/CT
J Nucl Med
(2008)
E. Sturm et al.
Fluordeoxyglucose positron emission tomography contributes to management of pediatric liver transplantation candidates with fever of unknown origin
Liver Transpl
(2006)
H. Balink et al.
F-18 FDG PET/CT in the diagnosis of fever of unknown origin
Clin Nucl Med
(2009)
C.P. Bleeker-Rovers et al.
Clinical value of FDG PET in patients with fever of unknown origin and patients suspected of focal infection or inflammation
Eur J Nucl Med Mol Imaging
(2004)

A. Kjaer et al.

Fever of unknown origin: prospective comparison of diagnostic value of ¹⁸F-FDG PET and ¹¹¹In-granulocyte scintigraphy

Eur J Nucl Med Mol Imaging

(2004)

J. Lorenzen et al.

Value of FDG PET in patients with fever of unknown origin

Nucl Med Commun

(2001)

L. Federici et al.

Value of (18)F-FDG-PET/CT in patients with fever of unknown origin and unexplained prolonged inflammatory syndrome: a single centre analysis experience

Int J Clin Pract

(2010)

M.J. Dong et al.

Value of 18F-FDG-PET/PET-CT in differentiated thyroid carcinoma with radioiodine-negative whole-body scan: a meta-analysis

Nucl Med Commun

(2009)

R.H. Huebner et al.

A meta-analysis of the literature for whole-body FDG PET detection of recurrent colorectal cancer

J Nucl Med

(2000)

D.T. Durack et al.

Fever of unknown origin—reexamined and redefined

Curr Clin Top Infect Dis

(1991)

R.G. Petersdorf

Fever of unknown origin. An old friend revisited

Arch Intern Med

(1992)

P. Whiting et al.

The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews

BMC Med Res Methodol

(2003)

D. Delbeke et al.

Procedure guideline for tumor imaging with 18F-FDG PET/CT 1.0

J Nucl Med

(2006)

H.R. Schelbert et al.

Procedure guideline for tumor imaging using fluorine-18-FDG. Society of Nuclear Medicine

J Nucl Med

(1998)

R.C. Delgado-Bolton et al.

Meta-analysis of the performance of ¹⁸F-FDG PET in primary tumor detection in unknown primary tumors

J Nucl Med

(2003)

J.P. Higgins et al.

Measuring inconsistency in meta-analyses

BMJ

(2003)

J. Zamora et al.

Meta-DiSc: a software for meta-analysis of test accuracy data

BMC Med Res Methodol

(2006)

Cited by (83)

Update on imaging in fever and inflammation of unknown origin: focus on infectious disorders
2024, Clinical Microbiology and Infection
Fever of unknown origin (FUO) and inflammation of unknown origin (IUO) are diagnostic challenges that often require an extensive work-up. When first-line tests do not provide any or only misleading clues, second-line investigations such as specialized imaging techniques are often warranted.
To provide an overview of the diagnostic value of imaging techniques that are commonly used in patients with FUO/IUO.
MEDLINE database was searched to identify the most relevant studies, trials, reviews, or meta-analyses until 31 March 2023.
The most important types of second-line imaging tests for FUO and IUO are outlined, including [⁶⁷Ga]-citrate single-photon emission computed tomography/computed tomography (CT), labelled leukocyte imaging, [¹⁸F]-fluorodeoxyglucose positron emission tomography CT ([¹⁸F]-FDG-PET), and whole-body magnetic resonance imaging. This review summarizes the diagnostic yield, extends on potential future imaging techniques (pathogen-specific bacterial imaging and [¹⁸F]-FDG-PET/magnetic resonance imaging), discusses cost-effectiveness, highlights practical implications and pitfalls, and addresses future perspectives. Where applicable, we provide additional data specifically for the infection subgroup.
Although many imaging examinations are proven to be useful in FUO and IUO, [¹⁸F]-FDG-PET/CT is the preferred second-line test when available as it provides a high diagnostic yield in a presumably cost-effective way.
Current situation and cost-effectiveness of 18F-FDG PET/CT for the diagnosis of fever of unknown origin and inflammation of unknown origin: A single-center, large-sample study from China
2022, European Journal of Radiology
¹⁸F-FDG PET/CT has an important role in the evaluation of fever of unknown origin (FUO) and inflammation of unknown origin (IUO). Our study was to investigate the current status of the inclusion of ¹⁸F-FDG PET/CT within FUO/ IUO diagnostic work-up and evaluate the cost-effectiveness of it in China.
A total of 741 FUO/IUO patients admitted to our hospital from January 2012 to December 2019 were retrospectively reviewed. The clinical characteristic, medical expenses to reach diagnosis and the proportion of definite etiological diagnosis achieved upon hospital discharge were compared between patients examined by ¹⁸F-FDG PET/CT (¹⁸F-FDG PET/CT group) and patients not examined by ¹⁸F-FDG PET/CT (non-¹⁸F-FDG PET/CT group).
The mean age, proportion of critically-ill patients, proportion of rheumatologic diseases, the number of examinations and hospitalisation days to reach diagnosis in the ¹⁸F-FDG PET/CT group were significantly higher than those in the non-¹⁸F-FDG PET/CT group. The mean medical costs of ¹⁸F-FDG PET/CT group were significantly higher than those of non-¹⁸F-FDG PET/CT group, whereas the proportion of definite etiological diagnosis achieved upon hospital discharge of ¹⁸F-FDG PET/CT group was significantly higher than that of non-¹⁸F-FDG PET/CT group. The mean hospitalisation days and mean medical costs before diagnosis were significantly lower in patients who undertook ¹⁸F-FDG PET/CT ≤ 7 days after hospital admission than those in patients who undertook ¹⁸F-FDG PET/CT > 7 days after hospital admission.
¹⁸F-FDG PET/CT is mostly used in critically-ill and hard-to-diagnose FUO/IUO patients currently in China, which may conceal its cost-effective advantage. While the early use of ¹⁸F-FDG PET/CT according to patient characteristics and etiological clues could help to reduce hospitalization stay, limit medical costs, thus producing its diagnostic effect to the great extent.
18F-FDG-PET/CT imaging in fever and inflammation of unknown origin
2022, Nuclear Medicine and Molecular Imaging: Volume 1-4
¹⁸F-FDG-PET/CT has gained an important place in the diagnostic work-up of patients with fever of unknown origin (FUO) and inflammation of unknown origin (IUO), which are defined as elevated body temperature or elevated inflammatory parameters for several weeks without an explanation, despite intensive investigation in an immunocompetent patient. Relying on the uptake of ¹⁸F-FDG-FDG in inflammatory cells, ¹⁸F-FDG-PET/CT may detect both infection and non-infectious inflammation, as well as malignancy, which all can cause FUO/IUO. Fever, CRP, and ESR can be used as parameters for the timing of ¹⁸F-FDG-PET/CT. When all of these are absent within the days before ¹⁸F-FDG-PET/CT, there is a high chance of non-contributory ¹⁸F-FDG-PET/CT. When performed at the right moment, ¹⁸F-FDG-PET/CT contributes to the final diagnosis in 48–62% of patients in meta-analyses. ¹⁸F-FDG-PET/CT could be cost-effective, as it may save up to 7000 Euros per patient when used at an early stage. When no abnormal ¹⁸F-FDG uptake is observed on PET/CT in a patient remaining without a final diagnosis, this may predict a higher chance of spontaneous resolution. When ¹⁸F-FDG-PET/CT is unavailable, gallium scintigraphy, or full body MR may be used as an alternative, but all of these are inferior to ¹⁸F-FDG-PET/CT. Labeled leukocyte scintigraphy can be useful as an alternative to ¹⁸F-FDG-PET/CT, particularly in patients with a high pre-test probability of infection. In the future, new tracers, and the combination of PET with MRI may increase the diagnostic value of PET in FUO/IUO.
The yield of F18 FDG PET-CT for the investigation of fever of unknown origin, compared with diagnostic CT
2021, European Journal of Internal Medicine
Citation Excerpt :
Nuclear medicine modalities are capable of early detection of disease activity at a cellular and molecular level and to distinguish between active and inactive disease [5]. 18-Fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) is an important imaging modality for the investigation of FUO [6]. Combined with contrast enhanced CT (PET-CT), more accurate localization and characterization of pathological uptake of FDG can be achieved.
18F-Fluoro-2-deoxy-D-glucose (FDG) positron emission tomography, with contrast enhanced CT (PET-CT), is recommended as a first or a second-line imaging method for the evaluation of patients with fever of unknown origin (FUO). We evaluated the yield of PET-CT vs. contrast enhanced CT (alone) for the diagnosis of classical FUO.
A single center, 8-year retrospective cohort study. All hospitalized patients who underwent PET-CT for the investigation of classical FUO between 1/2012-1/2020 were included. The final diagnosis, based on clinical, microbiological, radiological and pathological data available at the latest follow-up, at least six months after discharge, was determined. For each case, we determined whether the diagnosis would have been reached based on the CT scan alone, or based on the PET-CT (thus, defining PET-CT as necessary). We compared the overall sensitivity and specificity results for both PET-CT and CT scan. Variables that were found to be significantly associated with PET-CT necessity on univariable analysis were entered into a multivariable logistic regression analysis. The results of the regression model were reported in odds ratios (OR) and 95% confidence intervals (CI).
A total of 303 patients with classical FUO were referred for PET-CT. The final diagnoses included infectious diseases in 111/303 patients (36.5%), malignancies in 56/303 patients (18.4%) and non-infectious inflammatory conditions in 52/303 patients (17.1%). FUO resolved without diagnosis in 84/303 patients (28%). The overall sensitivity and specificity of the PET-CT scans were 88.7% and 80.9%, respectively, and for the CT scans were 75.2% and 90.2%, respectively. PET-CT had superior sensitivity vs CT (p=0.00) for all subgroups, with generally decreased specificity than CT for infections and inflammatory conditions. PET-CT was determined as necessary in 26% (79/303) of the patients. Endovascular infection, hematological malignancy and large vessel vasculitis were the only factors associated with PET-CT necessity on multivariable analysis.
PET-CT offers superior sensitivity with slightly decreased specificity for the diagnosis of classical FUO compared to diagnostic CT. We recommend PET-CT as the imaging modality of choice for patients with classical FUO, when endovascular infection, hematological malignancy or large vessel vasculitis are suspected.
PET/Computed Tomography in the Evaluation of Fever of Unknown Origin and Infectious/Inflammatory Disease in Pediatric Patients
2020, PET Clinics
Citation Excerpt :
FDG-PET/CT identified the cause of the fever in 48% of the patients and changed the treatment plan in 53% of the patients, with a sensitivity of 85.5% and a specificity of 79.2%.71 These pediatric articles reported FDG-PET/CT sensitivity of 80% to 100% 50,61,67 and specificity of 66.7% to 79.2%,61,67,71 similar to the pooled sensitivity of 82.6% and specificity of 57.8% in meta-analysis in the adult population.74 Lists of final diagnoses of children (up to 20 years old) with fever using and having positive FDG-PET/CT in published case reports, case series, reviews, and original articles categorized as infectious inflammatory diseases, noninfectious inflammatory diseases, and malignancy are detailed here.
Diagnostic performance of FDG PET/CT in critically ill patients with suspected infection: A systematic review and meta-analysis
2020, Journal of the Formosan Medical Association
Citation Excerpt :
Generally, these data support that FDG PET is a sensitive and practical imaging modality to identify sepsis origin in critically ill patients. Previous meta-analyses had evaluated the diagnostic performance of FDG PET/CT in the assessment of FUO33–35 and revealed a sensitivity 0.98, 0.85, 0.86, a specificity of 0.86, 0.52 and an AUC of 0.95 and 0.88, respectively. Also, FDG PET/CT had the best test performance comparing with other nuclear medicine images.35
Nuclear imaging, including gallium scintigraphy and fluorodeoxyglucose (FDG) positron emission tomography (PET), has been widely used to identify focus of infection in fever of unknown origin. However, little is known about its role in critically ill patients, who are usually with multiple inflammatory foci and unable to tolerate long image acquisition time. This systematic review aimed to evaluate the diagnostic performance of FDG PET for suspected infection in critically ill patients.
PubMed and Embase were searched up to July 24th, 2019 to identify studies evaluating the diagnostic performance of FDG PET for finding infection focus in critically ill patients following the PRISMA guidelines. The bivariate mixed-effects model was used to pool the measure for diagnostic performance. Publication bias was evaluated by Deeks' method.
A total of 4 studies with 87 patients were included. All the four studies evaluated FDG PET. Majority of the patients were either mechanically ventilated (76%) or shocked requiring vasopressors (61%). Test and transportation related adverse events were rare (2%). The summary sensitivity and specificity were 0.94 (95% CI, 0.79–0.99) and 0.66 (95% CI, 0.45–0.83), respectively. The AUC for summary ROC curve was 0.83.
FDG PET was a very sensitive tool with acceptable specificity for detecting the origin of infection in critically ill patients. However, current available studies have limitation in evaluating safety issue. Further research should investigate both benefit and risk of doing this test for this group of vulnerable patients.

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A meta-analysis of the value of fluorodeoxyglucose-PET/PET-CT in the evaluation of fever of unknown origin

Abstract

Background and purpose

Methods

Results

Conclusions

Introduction

Section snippets

Search strategy

Literature review

Study description

Discussion

Financial support

Conflict of interest

Eur J Intern Med

Eur J Radiol

J Clin Epidemiol

Eur J Intern Med

Am J Med

Am J Gastroenterol

Fever of unknown origin: the role of 18F-FDG PET/CT

J Nucl Med

Fluordeoxyglucose positron emission tomography contributes to management of pediatric liver transplantation candidates with fever of unknown origin

Liver Transpl

F-18 FDG PET/CT in the diagnosis of fever of unknown origin

Clin Nucl Med

Clinical value of FDG PET in patients with fever of unknown origin and patients suspected of focal infection or inflammation

Eur J Nucl Med Mol Imaging

Fever of unknown origin: prospective comparison of diagnostic value of 18F-FDG PET and 111In-granulocyte scintigraphy

Eur J Nucl Med Mol Imaging

Value of FDG PET in patients with fever of unknown origin

Nucl Med Commun

Value of (18)F-FDG-PET/CT in patients with fever of unknown origin and unexplained prolonged inflammatory syndrome: a single centre analysis experience

Int J Clin Pract

Value of 18F-FDG-PET/PET-CT in differentiated thyroid carcinoma with radioiodine-negative whole-body scan: a meta-analysis

Nucl Med Commun

A meta-analysis of the literature for whole-body FDG PET detection of recurrent colorectal cancer

J Nucl Med

Fever of unknown origin—reexamined and redefined

Curr Clin Top Infect Dis

Fever of unknown origin. An old friend revisited

Arch Intern Med

The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews

BMC Med Res Methodol

Procedure guideline for tumor imaging with 18F-FDG PET/CT 1.0

J Nucl Med

Procedure guideline for tumor imaging using fluorine-18-FDG. Society of Nuclear Medicine

J Nucl Med

Meta-analysis of the performance of 18F-FDG PET in primary tumor detection in unknown primary tumors

J Nucl Med

Measuring inconsistency in meta-analyses

BMJ

Meta-DiSc: a software for meta-analysis of test accuracy data

BMC Med Res Methodol

Fever of unknown origin: the role of ¹⁸F-FDG PET/CT

Fever of unknown origin: prospective comparison of diagnostic value of ¹⁸F-FDG PET and ¹¹¹In-granulocyte scintigraphy

Meta-analysis of the performance of ¹⁸F-FDG PET in primary tumor detection in unknown primary tumors