Place of 18F-FDG-PET in assessment of fever of unknown origin: a comparison with conventional scintigraphy
Fever of unknown origin (FUO) can be difficult to diagnose, and therefore remains a challenging problem for physicians. A thorough patient evaluation including patient history upon admission should be performed. This can steer the patient to a most suitable diagnostic imaging procedure, thus narrowing the cause of FUO and obtaining a faster diagnosis. Patients presenting with FUO to nuclear medicine departments are cases that are hard to diagnose because most often all of the other examination techniques have been exhausted without reaching definitive diagnosis. Scintigraphic procedures can be used to assess inflammatory or infectious foci in the whole body before anatomical changes are present. Conventional scintigraphic examinations for evaluation of FUO such as 67Gallium citrate (67Ga) and 111Indium-labelled leukocytes (LS) are still used. There is a certain debate on whether these methods should be performed given that 18F-fluoro-deoxyglugose positron emission tomography (18F-FDG-PET or FDG-PET) shows, most of the time, a higher sensitivity and specificity in detection of FUO when compared to the conventional methods. Additionally, FDG-PET has a much faster scanning time due to a shorter radiotracer half-life, thus being able to reach the diagnosis much quicker. The research performed on these methods is however limited to small patient groups, which further questions the feasibility of each technique in assessment of FUO.
Fever of unknown origin (FUO) was defined by Durack and Street in 1991 as a condition with fever equal or higher than 38.3°C continuing for at least 3 weeks and without determination of the condition following three consultations for outpatients, and three days of examinations for inpatients.1 FUO has a relatively high overall mortality percentage standing at 12-35%, thus fast identification of the cause of FUO is important.2 However, patients presenting with symptoms of FUO are most likely to be cases that are hard to diagnose.1 Almost half of those patients won’t have a definitive diagnosis.3 This is due to the advancements in diagnostic procedures and patients being able to seek medical advice before a 3 week mark, leading to harder to diagnose cases.3
Patients can vary in epidemiology, and therefore no single strategy can determine the source of the fever.3 However, there is a certain spectrum of most frequent etiologies that can cause the symptoms of FUO. There are five groups of diseases that can be responsible: malignances, infections, noninfectious inflammatory condition, miscellaneous, and undiagnosed causes.3 The most common category are patients presenting with infections.4 Malignancies are the second most common etiological cause of FUO, followed by noninfectious inflammatory disorders.5,6 Clinical studies have reported that in around half of the cases, final diagnosis cannot be determined using physical examinations, laboratory tests and first line imaging modalities.7,8,9 This is due to their limited specificity and sensitivity, especially during the early onset of disease.10 [18F]FDG-PET is usually performed following all first line examinations have been exhausted, and without the results of definitive diagnosis.11
The purpose of this non-exhaustive literature review is to examine the available information regarding the use of [18F]FDG-PET in assessment of FUO. This paper will focus on the place of this technique in evaluation of FUO, and its characteristics. Secondly, it will compare this modality against 67Ga scintigraphy, which is still used for FUO examination. Lastly, it will present the available data on 111In-labelled leukocytes scintigraphy in contrast with FDG-PET.
EVALUATION OF FEVER OF UNKNOWN ORIGIN
The diagnostic approach for assessment of FUO has not yet been standardised.12,13,14
However, to accurately evaluate the cause of FUO, it is important to begin with taking a detailed history. Thorough and consistent patient assessment is very important, and this should be based on the individual rather than standardised evaluation.15 A complete physical examination should be performed, and repeated at each encounter to minimise the possibility of omitting a vital detail. The next step would be to perform laboratory studies including urinalysis, which can give a clue and guidance for further evaluation.3 Imaging studies are used to localise the possible cause of the high temperature, and are selected in consideration of the previously performed examinations, the ALARA (as low as reasonably achievable) principle, availability, and cost.3 Ultrasonography, and x-ray studies are mostly selected as the first step, followed by computed tomography (CT) and magnetic resonance imaging (MRI) examinations. All of them have various sensitivity and specificity range, and are used in accordance to symptoms, and knowledge of potential causes.3 Sonography can be helpful in evaluating abdomen and pelvis, due to these areas being common for infections. CT assessments are excellent in detection of small nodules, tuberculosis, or mycobacterial or fungal infections.16 However, a relatively high percentage of false-positive results have been reported in a prospective study which suggests a more careful evaluation when using this modality for chest related assessments.5 MRI modality is used in a small number of cases, mostly in suspected meningitides, vertebral brucellosis, and inflammatory diseases in the pelvis. Additionally, there is limited availability of studies on MRI as a whole-body assessment for FUO which presently limits this examination technique.3
The previously mentioned modalities are capable of showing anatomical changes following inflammation or malignancy. However, they are limited when it comes to evaluation of the early stage of disease. In addition to this disadvantage is the ability to image only a certain part of the body, therefore omitting a possible cause of the origin of the condition.3 PET imaging can play an important role in diagnosis of FUO because it fulfills the above mentioned criteria. Moreover, it shows uptake in inflammatory cells, tumors, and granulation tissues which are the primary concerns for patients with FUO.18
The ability of imaging patients presenting with FUO using PET technology is possible due to the administered radiotracer. FDG used in PET imaging is a non-physiological glucose analogue, and it follows the glycolytic pathway of glucose molecule.19 It accumulates in cells via cell surface transporters, and then undergoes transformation to FDG-6-phosphate by a glycolytic enzyme.19 Certain cells require high rate of glycolysis to function. The increased rate of glycolysis in the leukocytes upon activation demonstrates that their primary source of energy is glucose molecule. This allowed for implementation of FDG into clinical use for assessment of chronic and acute inflammatory processes.19 Upon intravenous administration of 18FDG the PET camera can locate spots with enhanced metabolism as a result of detection of positron emission of the radiotracer. The hypermetabolic cells can represent malignant or inflammatory cells which can help to diagnose infectious diseases.20
PET IMAGING VERSUS 67Ga SPET
Many other radiopharmaceuticals have been used to evaluate FUO, such as 99mTcHMPAO-leukocytes, antigranulocyte antobodies, and the most common In-111 oxine leukocytes (LS), and 67Gallium citrate (67Ga).3 The nuclear medicine imaging technique using 67Ga is able to assess inflammatory or infectious foci of the whole body. However, this method has some drawbacks such as long waiting times prior to imaging, and a high radiation dose to the patient.
Two studies have been conducted investigating the difference between the use of [18F]FDG-PET, and 67Ga Citrate for assessment of FUO.
Blockmans et al used these two methods after a thorough evaluation of 58 patients using written guidelines.21 Both of them were scheduled as a second level tests following first-step examinations that did not yield any diagnostic clues, such as history taking, clinical assessment, laboratory tests, chest x-rays, and abdominal echography. Subsequent tests were performed after obtaining results from gallium and PET scintigraphy. Since 67Ga had limited availability at this site, PET imaging was scheduled as the first examination. Therefore, in the event of patients’ spontaneous symptom resolution or an established diagnosis with PET imaging, the gallium scintigraphy was cancelled leading to narrowing the patient number to forty for this study. For FDG-PET assessment a CTI-Siemens 931/08/12 camera, and a dose of 6.5 MBq/kg were used. The injection was intravenous, and the scan performed one hour post-injection. Patient was required to fast for ≥6 hours before the procedure. For a 67Gallium citrate scan 75 MBq was used and imaging commenced 72 hours post intravenous injection following bowel preparation the evening prior to reduce the normal radiotracer uptake in the colon. A large field of view and a medium energy collimators were used on a Siemens camera. The findings of both imaging techniques were compared against each other based on forty patients that underwent both imaging techniques. The 67gallium was helpful in 25% of the 40 patients. Meanwhile, [18F]FDG-PET contributed to diagnosis in 35% of those patients. Additionally, all of the cases with abnormal foci on a gallium scan were also detected by a PET scan. The abnormal, and noncontributory to diagnosis images were 42% for both techniques. The results are represented in Table 1 which also includes the diagnostic category, and normal findings percentage of both scans. The PET imaging was recommended to replace gallium scintigraphy for the assessment of FUO if this examination is available in the institution.
TABLE 1. The contribution of [18F]FDG-PET and 67Ga scintigraphy for assessment of FUO in forty patients. Adapted from “clinical value of [18F]fluoro-deoxyglucose positron emission tomography for patients with fever of unknown origin” by Blockmans D, Knockaert D, Maes A, et al. Clin Infect Dis. 2001;32:191-6.
Another prospective study consisting of twenty patients was performed by Meller et al. For this study SPET was used for 67gallium imaging, and a double-head coincidence camera for PET.22 Out of the 20 patients only 18 were scanned using both techniques. The results showed that 55% of them were able to obtain final diagnosis upon FDG-PET imaging which was much higher when compared with gallium scans. The positive predictive value (PPV) for FDG-PET was 92%, and the negative predictive value (NPV) was 75%, as oppose to gallium with 75% PPV, and 70% NPV. Additionally, FDG-PET was able to detect three patients with Takayasu’s aortitis, whereas 67Gallium scan showed true positive in only one of them. It was concluded that FDG-PET imaging should be used as a procedure of choice for evaluation of FUO.
Both of these studies are based on a small group sample size, which does not present with a significant comparison between both scans.
FDG-PET VERSUS 111IN-LABELLED LEUKOCYTES
Another possible mean of diagnosing focal inflammation or infection is via labeled leukocytes with In-111.3 Two prospective studies have been conducted using 111Indium labeled leukocytes (LS) SPET, and [18F]FDG PET.
Seshadri et al have recently compared the two modalities for evaluation of FUO.23 They aim was to assess the accuracy between those techniques. They were able to evaluate 23 patients presenting with symptoms of FUO. The PET scan was performed within seven days of having LS using a dedicated GE PET camera, and the 111In leukocytes were labelled using venous and anticoagulated blood with acid citrate dextrose (ACD), 6% W/V hydroxyethyl starch, 0.054% W/V tropolone solution, and 30 MBq of 111Indium Chloride. The scan commenced after 4 and 24 hours of intravenous administration with dual headed camera using medium energy collimators. The results of this study showed 65% (15) of the patients obtaining a final diagnosis upon histopathologic, microbiologic, or serologic tests, and defined clinical diagnostic criteria. An abnormal radiopharmaceutical uptake was reported in 3/23 (13%) patients using LS method with an overall sensitivity of 20%, and 100% specificity. Meanwhile, FDG-PET scans showed abnormality in 14/23 (61%) of patients. The sensitivity, and specificity were calculated as 86% and 78%, respectively. The study recommended using FDG-PET as the modality for assessment of FUO over LS due to its increased sensitivity, high specificity, early imaging, and higher spatial resolution.
On the other hand, the first performed study conducted by Kjaer and colleagues comparing LS and FDG-PET in assessment of FUO showed different results.24 They assessed prospectively nineteen patients. Both tests were scheduled no more than a week apart from each other, with LS being the first modality(KJAER). 111In leukocytes were labelled using venous blood, anticoagulant – citric acid glucose, 20-30 MBq of 111InCl3, and 0.0044 M tropolone. The images were obtained after 20-24 hours post-injection using medium energy collimators.
FIGURE 1. An example of false positive FDG-PET in the same patient (on the right), and a true negative on the LS scan (on the left). Adapted from “fever of unknown origin: prospective comparison of diagnostic value of 18F-FDG PET and 111In-granulocyte scintigraphy” by Kjaer A, Lebech A, Eigtved A, et al. Eur J Nucl Med Mol Imaging. 2004;31:622-626.
FDG-PET images were performed with a GE Advance scanner 1 hour post-intravenous injection of 400 MBq of 18F-FDG. The results showed that LS study was 71% sensitive, and 92% specific. Meanwhile, FDG-PET had a much lower results with sensitivity 50%, and specificity of 46%. The PPV and NPV for LS were 85%, and for FDG-PET 30% and 67%, respectively. The poor performance of FDG-PET attributed to high number of false positives, which led to drop in specificity. This can be represented in Figure 1, where LS showed a true negative result, and FDG-PET false positive indicating radiotracer uptake in the diaphragmatic crura and abdominal aorta. This study concluded that LS scans should be performed over FDG-PET for assessment of FUO.
The long, and unexplained fever can be challenging for the patient and the physician. Therefore, a thorough patient history taking, detailed physical examination together with the use of diagnostic modalities is essential to narrow down the many possible causes of FUO. Scintigraphy can provide helpful information regarding the localisation of the metabolic process. The literature presented here indicates the use of FDG-PET to be favourable in the assessment of FUO over the conventional scintigraphic techniques using 111In-labelled leukocytes and 67Ga Citrate SPET. The advantageous characteristics of [18F]FDG-PET such as faster imaging time, and increased spatial resolution also point out that this technique should be used as the primary scintigraphic technique. This conclusion of this paper reflects the general consensus in the literature. However, the research that has been conducted used relatively small groups, and only two prospective studies for both LS and 67Ga comparison with FDG-PET have been recently performed. In the future, prospective studies are recommended to have larger sample sizes. Additionally, new and more sensitive [18F]FDG-PET/CT cameras are becoming widely available, thus research on these cameras is warranted in order to reach a more accurate, and up to date conclusion.
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Gotthardt M, Bleeker-Rovers CP, Boerman OC, et al. Imaging of inflammation by PET, conventional scintigraphy, and other imaging techniques. J Nucl Med. 2010;51:1937-1949.
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Blockmans D, Knockaert D, Maes A, et al. Clinical value of [18F]fluoro-deoxyglucose positron emission tomography for patients with fever of unknown origin. Clin Infect Dis. 2001;32:191-196.
Meller J, Altenvoerde G, Munzel U, et al. Fever of unknown origin: prospective comparison of (18F)FDG imaging with a double-head coincidence camera and galium-67 citrate SPET. Eur J Nucl Med. 2000;27:1617-1625.
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Kjaer A, Lebech AM, Eigtved A, Hojgaard L. Fever of unknown origin: prospective comparison of diagnostic value of 18F-FDG PET and 111In-granulocyte scintigraphy. Eur J Nucl Med Mol Imaging. 2004;31:622-626.
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