International Journal of Infectious Diseases 19 (2014) 53–58

Diagnostic contribution of 18F-FDG-PET/CT in fever ofunknown origin§

Handan Tokmak a, Onder Ergonul b,*, Onur Demirkol b, Mustafa Cetiner b,Burhan Ferhanoglu b

a American Hospital, Istanbul, Turkeyb School of Medicine, Koc University, Istanbul, Turkey

A R T I C L E I N F O

Article history:

Received 23 July 2013

Received in revised form 31 August 2013

Accepted 9 October 2013

Corresponding Editor: Eskild Petersen,

Aarhus, Denmark

Keywords:

Fever of unknown origin (FUO)18F-FDG-PET/CT

Vasculitis

Inflammatory non-infectious disease

Imaging follow-up of FUO

S U M M A R Y

Objectives: Fever of unknown origin (FUO) remains one of the most compelling diagnostic issues in

medicine. We aimed to evaluate the potential clinical contribution of 18-fluoro-2-deoxyglucose positron

emission tomography/computed tomography (18F-FDG-PET/CT) in the identification of the underlying

cause of FUO.

Methods: Fifty consecutive patients (27 men and 23 women; age range 16–88 years) with FUO based on

the revised definition criteria were included in the study. A diagnostic protocol including biochemistry,

histopathology, and microbiological tests was performed and the patients were followed up. FDG-PET

was performed in 25 of the 50 patients (12 males and 13 females; age range 16–88 years) in order to

determine the etiology of the patient’s fever. PET-CT images were obtained with the Gemini Philips TF18F-FDG-PET/CT camera after a 60-min ‘standard uptake’ period following an injection of a mean 330

MBq (range 290–370 MBq) intravenous 18F-FDG.

Results: A total of 21 patients were available for analysis of the diagnostic contribution of PET/CT (two

patients were undiagnosed and two had non-contributory PET/CT findings). 18F-FDG-PET/CT was able to

precisely detect the cause of fever in 60% of the cases (n = 15). The accuracy, sensitivity, and specificity of

this imaging modality were 90.5%, 93.8%, and 80%, respectively. Among the cases with a true-positive18F-FDG-PET/CT finding (i.e., 15 cases), the identified underlying causes of FUO included localized

infection (n = 7), non-infective inflammatory process (n = 5), and malignancy (n = 3).

Conclusions: Further studies to confirm the high diagnostic yield of 18F-FDG-PET/CT observed in the

present study would lend support to the inclusion of this imaging modality in the initial diagnostic work-

up of patients with suspected FUO.

� 2013 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious

Diseases. All rights reserved.

Contents lists available at ScienceDirect

International Journal of Infectious Diseases

jou r nal h o mep ag e: w ww .e lsev ier . co m / loc ate / i j id

1. Introduction

Identification of the etiology of fever of unknown origin (FUO) iscrucial in guiding further diagnostic procedures and subsequentpatient management. The standard diagnostic approach includesrepeated laboratory tests, imaging procedures, and other conven-tional examinations, which are generally time-consuming andfrequently inconclusive. In this regard, it is important to note that a

§ This is an open-access article distributed under the terms of the Creative

Commons Attribution-NonCommercial-No Derivative Works License, which

permits non-commercial use, distribution, and reproduction in any medium,

provided the original author and source are credited.

* Corresponding author at: Koc University, School of Medicine, Infectious

Diseases Department, Istanbul, Turkey.

E-mail addresses: oergonul@ku.edu.tr, oergonul@gmail.com (O. Ergonul).

1201-9712/$36.00 – see front matter � 2013 The Authors. Published by Elsevier Ltd o

http://dx.doi.org/10.1016/j.ijid.2013.10.009

multitude of studies have been performed in the last decade toevaluate the diagnostic role of 18-fluoro-2-deoxyglucose positronemission tomography/computed tomography (18F-FDG-PET/CT) inFUO.1–7

Generally, these studies have emphasized the usefulness andadvantages of 18F-FDG-PET/CT in terms of providing betterdiagnostic accuracy as compared to other standard diagnosticapproaches, mostly likely owing to its ability to assess themorphology and functional characteristics of the tissues simulta-neously.8–13 The metabolic properties of 18F-FDG allow 18F-FDG-PET/CT to reflect the status of the intracellular glucose metabolismsuccessfully. This property of 18F-FDG-PET/CT is especially usefulfor elucidating equivocal structural abnormalities through assess-ment of the metabolic activity, or for defining inflammatoryprocesses that are difficult to examine through the use ofconventional imaging modalities.14–16

n behalf of International Society for Infectious Diseases. All rights reserved.

H. Tokmak et al. / International Journal of Infectious Diseases 19 (2014) 53–5854

In this study, the predictive diagnostic value of 18F-FDG-PET/CTimaging in FUO was explored.

2. Patients and methods

2.1. Patients

A total of 50 consecutive patients admitted to the AmericanHospital between 2008 and 2012 with a clinical suspicion of FUOwere included in this retrospective observational study. Twenty-five of the 50 patients underwent PET/CT examination at thediscretion of the physician, without the use of a specific protocol.Patient data were retrieved from the hospital records.

FUO was defined as a temperature greater than 38 8C on severaloccasions, a duration of illness of more than 3 weeks, and noidentified diagnosis despite 1 week of inpatient investigation.10,11

The latter criterion has recently been modified and is nowgenerally interpreted as no established diagnosis after adequateinpatient or outpatient evaluation.17 Patients with an activemalignancy, neutropenia, or nosocomial infections were notincluded in the study.

2.2. Basic diagnostic evaluation

After a comprehensive history was obtained (includinginformation on travel, occupation, and sexual history) and aphysical examination was performed, a series of laboratoryinvestigations for FUO was also carried out for all participants,including routine blood tests (complete blood count, erythrocytesedimentation rate (ESR), renal and hepatic function tests,electrolytes, creatinine phosphokinase, and lactate dehydroge-nase), urinalysis, chest radiography, abdominal ultrasonography,Brucella serum tube agglutination, Gruber–Widal agglutination,peripheral blood smear, anti-nuclear and anti-neutrophilic cyto-plasmic antibodies, rheumatoid factor, and blood and urinecultures. When deemed necessary, the following tests were alsodone: cultures other than blood and urine, serologic tests forcytomegalovirus (CMV) IgM, Epstein–Barr virus (EBV), Salmonella,Brucella, Coxiella burnetii, Toxoplasma, rubella, herpes, andhepatitis A, B, and C viruses, echocardiography, computerizedtomography (CT), magnetic resonance imaging (MRI), histopatho-logical examination, and peripheral smear for malaria. PET/CT wasused at the discretion of the physician without a specific protocol.The final diagnosis was based on the results of histopathology,microbiological or serologic assays, and/or long-term clinical andimaging follow-up.

2.3. 18F-FDG-PET/CT imaging

In those undergoing a PET/CT examination, whole body scanswere performed (defined as from the top of the head through themid-thigh), and if clinically indicated, was extended to total bodyimaging, including the extremities. Additionally, a low-dose CTwas performed in order to process attenuation correction (CT-AC),or it was used for anatomical co-registration of PET findings. 18F-FDG-PET/CT images were acquired 60 min after the intravenousinjection of 18F-FDG, using an 18F-FDG-PET/CT combined with athird-generation multi-slice spiral CT scanner with a dedicatedfull-ring PET scanner, which had a high count rate capabilitylutetium yttrium oxyorthosilicate (LYSO)-based camera with time-of-flight (TOF) technology. Emission scans of 18F-FDG-PET/CT wereacquired in 3D mode, from head to mid-thigh. PET and CT images(non-corrected and attenuation-corrected) were evaluated in therotating maximum-intensity projection and in the cross-sectionalplanes view (transverse–sagittal–coronal). The images withincreased focal uptake with higher intensity than the surrounding

tissues, not corresponding to physiological distribution of 18F-FDG,were defined as positive.

2.4. Interpretation of data

Patients were followed-up for 12 months. True-positivity (TP)was defined as an 18F-FDG-PET/CT study demonstrating a focal 18F-FDG-positive lesion, which subsequently proved to be causative ofthe FUO. False-positivity (FP) was defined as hypermetabolicactivity that could not be associated with an inflammatory/infectious process causing FUO at the time of the initialexamination or during the 12-month follow-up period. Normalfindings with a physiological FDG accumulation were recorded astrue-negative (TN) when no localized disease process wasdiagnosed and there were no findings of disease identified duringfollow-up. On the other hand, in the event that a focal infectiousprocess, non-infectious inflammatory process, or malignancy wasidentified during clinical investigation within the 30-day periodfollowing a negative 18F-FDG-PET/CT, the outcome was interpretedas false-negative (FN). The diagnostic accuracy, sensitivity, andspecificity of the test were defined as follows: diagnostic accuracy,(TP + TN)/(TP + TN + FP + FN); sensitivity, TP/(TP + FN); specificity,TN/(FP + TN).

3. Results

The characteristics of the patients who underwent PET/CTimaging and the diagnostic contribution of PET/CT are presented inTable 1. Of the 25 patients, four were not available for diagnosticvalue estimations. In two of these, a final diagnosis could not beestablished, thus they were categorized as ‘undiagnosed’. One ofthe patients in the ‘undiagnosed’ category had bilateral hypermet-abolic mediastinal lymphadenopathy and increased FDG uptake inthe mediastinal lymph nodes, but did not consent to a biopsy. Theother patient, who had anemia in conjunction with fever, had anegative PET/CT scan (except for non-specific findings), and thefever subsided in several weeks without an established definitivediagnosis. Two other patients who were categorized as ‘non-contributory’ due to negative PET/CT scans (except for non-specificfindings) were subsequently diagnosed with Still’s disease withouta specific focus.

18F-FDG-PET/CT was able to detect the cause of fever preciselyin 60% (n = 15) of the patients. Among the 21 patients in whom thediagnostic role of 18F-FDG-PET/CT could be assessed, the resultswere categorized as follows: 15 true-positive, four true-negative,one false-positive, and one false-negative. Thus, the estimatedaccuracy, sensitivity, and specificity of 18F-FDG-PET/CT were 90.5%,93.8%, and 80%, respectively.

Among the true-positive cases, the following underlying causesof FUO were identified: localized infection in seven patients, non-infective inflammatory process in five patients, and malignancy inthree patients. The subsequent diagnoses in true-negative casesincluded one patient with a chronic urinary tract infection with nofocal 18F-FDG accumulation, one patient with FMF (FamilialMediterranean fever), and two other patients with spontaneousdisappearance of fever. In these latter cases, there were noadditional findings suggestive of an etiological factor during theclinical follow-up. One patient with an initial positive 18F-FDG-PET/CT result was subsequently categorized as ‘false-positive’. Thispatient, who had increased skeletal uptake and multiple lymphnodes, was later diagnosed with anti-phospholipid syndrome andwas treated successfully with corticosteroid therapy. Also, therewas one false-negative result in a single patient with an ultimatediagnosis of temporal arteritis with negative 18F-FDG-PET/CTfindings.

Table 1Patient characteristics and the results of diagnostic procedures

Age, years Gender Imaging findings Results of additional relevant

diagnostic procedures

Contribution of PET/CT Final diagnosis Result Disease group

81 M Diffuse bone marrow activity increase Inconclusive CT findings Non-contributory Temporal arteritis FN Rheumatologic

55 F Increased spleen activity plus low FDG

avid non-specific lymph nodes

Inconclusive CT findings Improved diagnostic approach, many

causes if fever excluded

Anti-phospholipid syndrome FP Rheumatologic

65 M Inhomogeneously increased skeletal

and diffuse bone marrow uptake

None Improved diagnostic approach Still’s disease Non-contributory Rheumatologic

62 F Increased bone marrow plus spleen

activity

None Non-contributory Undiagnosed (anemia but no reason

found for fever), spontaneous recovery

Undiagnosed N

76 F Symmetrical hypermetabolic

mediastinal lymph nodes

Mediastinal lymph nodes Patient did not accept the biopsy

(otherwise, PET/CT would guide for

biopsy site)

Undiagnosed Undiagnosed N

33 F Heterogeneous increase in bone

marrow and spleen activity

None Improved diagnostic approach Still’s disease Non-contributory Rheumatologic

75 M Non-specific None Non-contributory Chronic urinary tract infection TN Infectious

80 F Physiological FDG distribution None Improved diagnostic approach (by

excluding fever causes)

Not diagnostic TN N

81 F Physiological FDG distribution Inconclusive CT findings Improved diagnostic approach (by

excluding fever causes)

Not diagnostic TN N

45 M Physiological FDG distribution Inconclusive CT findings Improved diagnostic approach (by

excluding fever causes)

Familial Mediterranean fever TN Rheumatologic

58 F Periarticular uptake Inconclusive CT findings Leading criteria to final diagnosis Polymyalgia rheumatica TP Rheumatologic

58 M Vascular prosthesis (20 years ago) Inconclusive CT findings Aided in diagnosis and guided for

surgical approach

Infective prosthetic graft TP Infectious

37 M Pleural activity Inconclusive CT findings (pleural

thickening)

Guided biopsy Pleuritis TP Infectious

70 F Sub-hepatic focal uptake Inconclusive CT findings (history of

abdominal surgery)

Aided in diagnosis and guided for

treatment (removal of catheter)

Shunt infection TP Infectious

56 F Maxillary uptake CT findings of sinusitis Other more likely fever causes were

excluded, determined the need for

antibiotic treatment

Sinusitis TP Infectious

55 M L3–5 soft tissue Previous vertebral operation plus

pacemaker (contraindication for MRI)

Guided biopsy Spondylitis TP Infectious

66 F Lung uptake Inconclusive CT findings Guided biopsy Tuberculosis TP Infectious

60 F Soft tissue uptake None Guided biopsy Panniculitis TP Infectious

54 M Hypermetabolic cervical mediastinal

lymph nodes

None Guided biopsy and established

diagnosis (at the very early stage)

Acute myeloid leukemia TP Neoplastic

24 F Hypermetabolic brain lesions plus

multiple hypermetabolic lymph nodes

Complicated CT findings Showed brain lesions plus guided

biopsy plus helpful in the evaluation of

treatment response

Lymphoma and tuberculosis TP Neoplastic

16 M Heterogeneous bone marrow uptake

plus hypermetabolic skin lesion

None Guided biopsy and established

diagnosis

Acute myeloid leukemia TP Neoplastic

75 M Tendon adjunction None Guided biopsy Enthesopathy TP Rheumatologic

53 F Vasculitis Inconclusive CT findings Guided biopsy Giant cell vasculitis TP Rheumatologic

62 F Soft tissue uptake in deep gluteal fat

tissue

None Guided for identification of the biopsy

site

Panniculitis TP Rheumatologic

88 M Increased periarticular uptake None Guided biopsy Polymyalgia rheumatica TP Rheumatologic

F, female; FDG, fluorodeoxyglucose; FN, false-negative; FP, false-positive; M, male; MRI, magnetic resonance imaging; N, None; PET/CT, positron emission tomography/computed tomography; TN, true-negative; TP, true-positive.

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H. Tokmak et al. / International Journal of Infectious Diseases 19 (2014) 53–5856

The final diagnoses among the other 25 patients admitted to ourinstitution during the study period who did not undergo PET/CTexamination were as follows: infection in 13 patients, rheumato-logic disease in six patients, and malignancy in four patients; twopatients remained undiagnosed.

4. Discussion

The diagnostic performance of 18F-FDG-PET/CT in detecting afocal etiology in patients with FUO is generally assessed based oncertain parameters, such as the sensitivity, specificity, positivepredictive value (PPV), and negative predictive value (NPV). Theinitial work-up usually includes standard laboratory, histopathol-ogy, microbiological–immunological assays, or conventional ana-tomic imaging modalities, i.e. ultrasound, CT, and MRI.Unfortunately, these standard approaches generally exhibit arelatively low sensitivity and specificity, particularly during theearly stages of disease.8–10 In this study, the estimated diagnostic

Figure 1. 18F-FDG-PET/CT images of a patient with a histologic

accuracy, sensitivity, and specificity of 18F-FDG-PET/CT for FUOwere 90.5%, 93.8%, and 80%, respectively. The 18F-FDG-PET/CTdemonstrates better accuracy owing to its ability to carry outmorphological and functional assessments concomitantly, incontrast to the conventional diagnostic modalities.18–22 18F-FDG-PET/CT facilitates an early diagnosis not only by indicatingthe best biopsy site, but also through altering the traditionalclinical perspective by providing morphological and functionalhybrid imaging of the whole body.23 In complicated patients inparticular, determining the underlying cause of FUO is often avexing diagnostic challenge for the clinician, as was the case withour Hodgkin lymphoma patient who also had systemic tuberculo-sis. In this challenging case, 18F-FDG-PET/CT revealed positivefindings in the brain and supra- and infra-diaphragmatic lymphnodes, along with heterogeneous lung uptake and hepatospleno-megaly. In this patient, laboratory findings were non-specific butthey suggested the presence of lymphoma. Bone marrow andlymph node pathology confirmed a diagnosis of diffuse large B cell

ally established diagnosis of acute monoblastic leukemia.

H. Tokmak et al. / International Journal of Infectious Diseases 19 (2014) 53–58 57

lymphoma. Tuberculosis had initially been suspected based onpulmonary findings and accompanying encephalopathy, butbronchoscopy revealed bronchopulmonary lavage fluid withnegative Ziehl–Neelsen staining. Pathological examination of theaxillary lymph nodes showed necrotic granulomas and diffuseinvasion of lymphocytes with atypical nuclei. Patients withmalignant lymphoma are known to be vulnerable to tuberculosis,and 18F-FDG-PET/CT imaging has provided a major contribution tothe final diagnosis by indicating the best possible biopsy sites andshowing diffuse pathological findings. Furthermore, 18F-FDG-PET/CT findings have subsequently proved to be crucial in theevaluation of the outcome of treatment.

The diagnosis of acute monoblastic leukemia (AML) as theetiology of FUO requires a high index of suspicion due to itsinfrequent occurrence and non-specific symptomatology. Twopatients in our series were diagnosed with AML (Figure 1). They

Figure 2. 18F-FDG-PET/CT images revealed diffusely increased 18F-FDG uptake in a circ

subclavian, and common iliac arteries.

had vague and non-specific symptoms such as fever, fatigue,weight loss or loss of appetite, shortness of breath, and anemia.18F-FDG-PET/CT was extremely useful in the diagnosis of thesepatients through monitoring 18F-FDG in the skin lesions and bonemarrow.

Specifically, 18F-FDG-PET/CT has been useful in both positive andnegative cases. The two patients showing an inhomogeneousincreased 18F-FDG uptake throughout the axial and appendicularskeleton had no further evidence of pathology at biopsy. Accordingto previous reports, increased bone marrow 18F-FDG uptake may bea consequence of interleukin-dependent upregulation of glucosetransporters rather than the underlying etiology of FUO.21 Two of thepatients with increased 18F-FDG uptake throughout the axial andappendicular skeleton were diagnosed with Still’s disease. 18F-FDG-PET/CT provided useful information for further management beyondthe traditional medical perspective, although it did not contribute

umferential fashion along the aorta and its major branches, including the carotid,

H. Tokmak et al. / International Journal of Infectious Diseases 19 (2014) 53–5858

specifically to the final diagnosis. An increased FDG uptake in themediastinal lymph nodes was found in another patient (female,aged 76 years). However, this patient did not consent to abiopsy, thus a final diagnosis could not be established. Nevertheless,in non-specific inflammatory processes involving soft tissues orlymph nodes, increased metabolic activity has been describedpreviously.16

Giant cell vasculitis may be associated with non-specificsymptoms, as in one of the patients in our series (Figure 2), andit comprises 17% of all FUO cases.10 In our group, the correspondingfigure for giant cell vasculitis was 8%. A high NPV has previouslybeen reported for FDG-PET/CT in the diagnosis of large vesselvasculitis, with a sensitivity ranging between 77% and 92% andspecificity ranging between 89% and 100%.24–27 Even in this group,where the possibility of focal disease is ruled out, 18F-FDG-PET/CToffers a useful contribution to the diagnostic work-up of largevessel vasculitis.

In the present study, 18F-FDG-PET/CT has been found to providevaluable information, facilitating a final diagnosis or ruling out afocal pathology in patients with FUO. Even a negative PET/CT wasuseful in terms of guiding further management strategies. Thepresent findings reported for 21 patients with high accuracy,sensitivity, and specificity provides further supporting evidence tothe already existing literature data for the use of this specificimaging modality in suspected FUO cases.28,29 For example, in aprospective multicentre study, Keidar et al.5 evaluated the role of18F-FDG-PET/CT in 48 patients with FUO; in that study PET/CTidentified the underlying cause of the fever in 46% of the studypopulation and contributed to the diagnosis or exclusion of a focalpathological etiology of the febrile state in 90% of patients, with ahigh NPV (100%) for the assessment of FUO. Together with theresults reported in a multitude of retrospective studies, the highsensitivity and specificity of FDG-PET/CT suggests that thisimaging technique represents a promising diagnostic procedurefor the detection of the underlying cause of FUO. In this regard, itmay be worth looking at the PPV/NPV rates reported by Balinket al.,2 Pelosi et al.,13 and Crouzet et al.,29 which were 93%/100%,85%/91%, and 93%/100%, respectively.

Several studies have suggested a higher cost-effectiveness forPET/CT in suspected FUO when used in the early stages.30

Considering its high cost, the routine use of PET/CT for thisindication is unlikely to occur in the near future. On the other hand,the liberal use of this approach in centers like ours where PET/CT isavailable could provide useful information in the management ofFUO cases. Furthermore, the use of this modality for the evaluationof patients with FUO would not raise serious concerns aboutradiation exposure, since the CT component of PET/CT imaging isassociated with a low radiation exposure, which is withinacceptable limits and similar to the dose a typical patient withFUO would receive during routine radiological investigations.

In conclusion 18F-FDG-PET/CT has an incremental diagnosticvalue in the diagnosis and management of FUO. In the future, 18F-FDG-PET/CT may well be included in the initial diagnostic work-upfor the investigation of the etiology of FUO.

Conflict of interest: The authors declare that they do not have anyconflict of interest.

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