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PET Imaging of Infection

Written By

Christopher J. Palestro

Submitted: 19 February 2023 Reviewed: 21 February 2023 Published: 13 April 2023

DOI: 10.5772/intechopen.110633

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Pericarditis Diagnosis and Management Challenges Edited by Alexander Berezin

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Pericarditis - Diagnosis and Management Challenges

Edited by Alexander E. Berezin

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Abstract

Nuclear medicine has played an important part in the diagnosis of infection for 50 years. Gallium-67 citrate was one of the first radionuclides used for diagnosing and localizing infection. The development of techniques for radiolabeling leukocytes and monitoring their migration to foci of infection was a significant advance. More recently, investigators have worked on developing positron-emitting radiopharmaceuticals for diagnosing infection. Positron emission tomography (PET) provides high-resolution three-dimensional images, facilitating precise localization of radiopharmaceutical uptake. Semiquantitative analysis could facilitate the differentiation of infectious from noninfectious conditions and could be used to monitor treatment response. Not surprisingly, the first PET agent investigated was fluorine 18-fluorodeoxyglucose (18F-FDG). Although 18F-FDG has proved to be invaluable for diagnosing infection, it is not specific, and also accumulates in neoplasms, and noninfectious inflammatory conditions. Considerable effort has been devoted to developing PET radiopharmaceuticals that are specific, or at least more specific than 18F-FDG, for infection. Investigators have explored the potential of leukocytes labeled in vitro with various PET radiopharmaceuticals, gallium-68 citrate, gallium-68 labeled peptides, iodine-124 fialuridine, and 18F-fluorodeoxysorbitol. This chapter reviews the role of 18F-FDG for diagnosing infection and monitoring treatment response and other PET agents whose potential for diagnosing infection has been studied.

Keywords

  • cardiovascular infections
  • 18F-FDG
  • 18F-FDS
  • 124FIAU
  • FUO
  • gallium
  • osteomyelitis
  • sarcoid
  • spondylodiscitis
  • tuberculosis
  • zirconium

1. Introduction

Infection is a major cause of patient morbidity and mortality throughout the world. The diagnosis of infection can be challenging and imaging studies are often used for confirmation and localization. Radiological tests, such as x-rays, ultrasonography, computed tomography, and magnetic resonance imaging, reflect structural alterations in tissues and organs produced by a combination of the infection and the host’s response to the infection. Structural changes take time to evolve and there is a delay between the molecular events of the disease process itself and the appearance of structural changes on radiologic imaging. Nuclear medicine imaging agents can be taken up directly by cells, tissues, and organs, or can be attached to native substances that then migrate to an inflammatory focus. These agents reflect physiological changes in the inflammatory process and can identify abnormalities before the development of structural changes [1]. For many years, the single photon emitting radiopharmaceuticals, gallium-67 citrate, and in vitro labeled leukocytes were the mainstay of nuclear medicine imaging of infection. Positron emission tomography (PET) has several advantages over single photon imaging. PET provides high-resolution three-dimensional images of the whole body facilitating precise localization of radiopharmaceutical uptake. Semiquantitative analysis could facilitate the differentiation of infectious from noninfectious conditions and could be useful for monitoring response to treatment. In view of the advantages of PET over single photon imaging as well as the proliferation of clinical PET over the past 25 years, it is not surprising that investigators have turned their attention to developing PET radiopharmaceuticals for diagnosing infection. The first and most extensively studied of these agents is fluorine-18 fluorodeoxyglucose (18F-FDG). Developed primarily for oncology, 18F-FDG uptake in inflammation was soon recognized. While such uptake could confound study interpretation in patients with tumors, the possibility of 18F-FDG for imaging infection was exploited [2]. The potential of human leukocytes labeled in vitro with 18F-FDG, copper-64 (64Cu), and zirconium-89 (89Zr) for imaging infection has also been investigated. Other PET agents that have been studied include gallium-68 (68Ga) citrate, iodine-124 (124I)-filauridine, fluorine-18 fluorodeoxysorbitol (18F-FDS), and 68Ga labeled peptides.

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2. 18F-FDG

Cellular uptake of fluorodeoxyglucose, which is a structural analog of 2-deoxyglucose, is governed by three mechanisms: passive diffusion, active transport by a Na1-dependent glucose transporter (GLUT), and via GLUT-1 through GLUT-13 transporters. Once inside the cell, it is phosphorylated to 2’-FDG-6 phosphate by the hexokinase enzyme. Unlike glucose-6-phosphate, 2’-FDG-6 phosphate is not a substrate for the enzymes of the glycolytic pathway or the pentose–phosphate shunt. It is trapped intracellularly but is not metabolized, and does not diffuse back into the extracellular space [3].

The normal distribution of 18F-FDG includes the brain, myocardium, and urinary tract. Thymic uptake, particularly in children, has been observed. Gastric and bowel activity are variable. Liver, spleen, and bone marrow uptake generally are low-grade (Figure 1) [4]. The small 18F-FDG molecule enters poorly perfused areas rapidly, so imaging can be performed within 1–2 hours after administration. Skeletal uptake usually normalizes within 3–4 months after trauma or surgery, and degenerative bone changes ordinarily show only mildly increased uptake, which are advantageous when musculoskeletal infection is a concern [5]. Over the past two decades, 18F-FDG has assumed an increasingly important role in molecular imaging of infection.

Figure 1.

Normal 18F-FDG maximum intensity projection image. There is brain, myocardial, liver, spleen, and urinary tract activity. Faint bone marrow uptake is present.

2.1 Musculoskeletal infection

18F-FDG has proved to be very useful for diagnosing osteomyelitis (Figure 2). In one systematic review, 18F-FDG PET had a pooled sensitivity of 0.92 (95% CI: 0.87–0.96) and a pooled specificity of 0.92 (95% CI: 0.87–0.96) for the diagnosis of osteomyelitis, for a positive likelihood ratio of 9.77 (95% CI: 5.99–15.95) and a negative likelihood ratio of 0.12 (95% CI: 0.07–0.20). The area under the summary receiver operating characteristics curve was 0.97 [6]. In another systematic review, 18F-FDG PET had a pooled sensitivity of 0.96 (95% CI: 0.88–0.99) and a pooled specificity of 0.91 (95% CI: 0.81–0.95) for diagnosing chronic osteomyelitis [7].

Figure 2.

Sacral osteomyelitis. There is 18F-FDG uptake in a sacral decubitus ulcer extending into the distal sacrum (arrow).

2.1.1 Spondylodiscitis

The role of 18F-FDG in the diagnosis of spondylodiscitis has been extensively studied. The pooled sensitivity and specificity of 18F-FDG PET/PET-CT were 97% and 88% in one meta-analysis [8]. In another meta-analysis, the pooled sensitivity was 94.8% and the pooled specificity was 91.4% (Figure 3) [9] . In intraindividual comparisons, 18F-FDG has outperformed bone and gallium-67 scintigraphy both alone and in combination [10, 11].

Figure 3.

Spondylodiscitis. There is abnormal 18F-FDG activity in the T12-L1 vertebrae corresponding to erosive changes on the CT component, with extension into the prevertebral space (arrow).

Postoperative spondylodiscitis often has an indolent, nonspecific presentation. Prompt diagnosis is imperative because a delay may lead to involvement of the bone, epidural space, and paravertebral soft tissues, and may necessitate hardware removal, which can lead to instability and pseudoarthrosis [12]. In a meta-analysis of 18F-FDG for diagnosing postoperative spondylodiscitis, the summary AUC for spondylodiscitis was 0.92 in patients with versus 0.98 in patients without spinal hardware. False-positive results were more common in patients with than in patients without hardware (12.8% vs. 7%), presumably due to hardware-induced aseptic inflammation. Performing PET/CT rather than PET alone reduces hardware-associated false-positive results [8]. Analyzing uptake patterns may facilitate the differentiation between aseptic inflammation and infection. Confluent increased 18F-FDG uptake in soft tissue and bone immediately adjacent to the hardware at multiple contiguous levels is suggestive of infection, while focal uptake adjacent to one or two hooks, screws, or anchors, usually at the upper or lower aspects of the spinal hardware is more suggestive of noninfectious complications [13].

18F-FDG may be useful for monitoring treatment response in spondylodiscitis (Figure 4). Some investigators have reported that changes in standardized uptake value (SUV) reliably differentiate responders from nonresponders, while other investigators have observed that changes in uptake patterns are useful for monitoring treatment response [14, 15, 16, 17, 18, 19].

Figure 4.

Spondylodiscitis thoracic spine. On the pretreatment 18F-FDG PET/CT (left) there is intense uptake in the T2-T3 vertebrae (arrow). On the posttreatment study, performed about 3 months later, the abnormal uptake had resolved. Persistent esophageal activity (arrowhead) was thought to be secondary to a foreign body reaction or metastatic disease in this patient with esophageal carcinoma (reproduced with permission from Seminars in Nuclear Medicine: Raghavan M, Palestro CJ: Imaging spondylodiscitis: an update. 53:152-166. DOI: 10.1053/j.semnuclmed.2022.11.005).

2.1.2 Diabetic pedal osteomyelitis

Because diabetics can have a significant foot infection with few signs or symptoms and without mounting a systemic inflammatory response, the diagnosis of osteomyelitis can easily be overlooked [20]. Molecular imaging has always had an important role in the workup of these patients and data indicate that 18F-FDG is useful in this population. In one meta-analysis, the pooled sensitivity and specificity of 18F-FDG were 74% and 91%, respectively [21].

In another meta-analysis, the pooled sensitivity and specificity of 18F-FDG were 89% and 92%, respectively, which was similar to the pooled sensitivity and specificity of 99mTc-labeled leukocyte scintigraphy: 91% and 92%, respectively [22].

2.1.3 Periprosthetic joint infection

In a systematic review the pooled sensitivity and specificity of 18F-FDG-PET for diagnosing lower extremity periprosthetic joint infection (PJI) were 86% (95% CI: 82−90%) and 86% (95% CI: 83−89%), respectively [23]. In another systematic review, the pooled sensitivity and specificity of 18F-FDG-PET for lower extremity PJI were 82.1% (95% CI: 68.0−90.8%) and 86.6% (95% CI: 79.7−91.4%), respectively [24]. The authors noted that caution is warranted because results of individual studies were heterogeneous and could not be fully explored. These limitations are borne out by the inconsistent results reported in individual investigations over the years [25]. Different test probabilities, the inability to discriminate between infection and aseptic inflammation, and a lack of standardized interpretative criteria are obstacles to incorporating 18F-FDG-PET into the routine diagnostic imaging workup for PJI (Figure 5) [26].

Figure 5.

Asymptomatic knee arthroplasties. There is intense periprosthetic 18F-FDG around the right knee arthroplasty and to lesser extent around the left knee arthroplasty. The inability to be able to consistently discriminate between periprosthetic infection and aseptic inflammation, is a significant disadvantage of 18F-FDG.

Data on 18F-FDG for diagnosing PJI of shoulder arthroplasties are scant. In an investigation of 86 patients with suspected chronic PJI of the shoulder, the sensitivity and specificity of 18F-FDG PET/CT were 14% (3/22) and 91% (58/64), respectively [27].

2.2 Cardiovascular infections

The term cardiovascular infection encompasses a wide range of infections, including endocarditis, cardiac implantable electronic device (CIED), and prosthetic vascular graft infections. Diagnosis of these often life-threatening conditions can be challenging and 18F-FDG can play an important role in their diagnosis.

2.2.1 Infective endocarditis

Infective endocarditis (IE) is a life-threatening infection. In spite of advances in diagnosis and treatment, patients with IE still have high rates of morbidity and mortality. The diagnosis is based on modified Duke's criteria that classify patients into three categories: definite, possible, and rejected IE. The overall sensitivity of modified Duke’s criteria is approximately 80% [28, 29].

18F-FDG is a useful adjunct for diagnosing IE with a pooled sensitivity and specificity of 61% and 88%, respectively (Figure 6). It is especially useful in the setting of prosthetic heart valves. False-negative results are associated with lesions below the limits of res olution of current systems and antibiotic treatment for more than 1 week prior to imaging. False positive results can occur with postoperative inflammation during the first 2 months after implantation and in the presence of severe prosthetic valve thrombosis [30, 31].

Figure 6.

Infective endocarditis prosthetic aortic valve. 18F-FDG is especially useful for diagnosing infective endocarditis in patients with prosthetic heart valves.

2.2.2 Cardiac implantable electronic device infections

CIEDs, such as permanent pacemakers, cardioverter-defibrillators, and cardiac resynchronization systems, have become increasingly important in the management of cardiac disease. The number of devices implanted has increased over time, especially in older patients with more comorbidities, leading to higher infection rates [32].

18F-FDG is useful for diagnosing CIED infections (Figure 7). Besides diagnosing pacemaker pocket infection, 18F-FDG delineates the extent of infection and improves the diagnostic accuracy of the modified Duke’s criteria for CIED infection. It is useful for diagnosing left ventricular assist device infection, determining extent of infection, and monitoring treatment response [33, 34, 35, 36]. In a meta-analysis of nearly five hundred patients, the pooled sensitivity of 18F-FDG PET/CT for diagnosing CIED infection was 83% and the pooled specificity was 89%. For diagnosing pocket infection, pooled sensitivity and specificity were 96% and 97%, respectively. The test was less sensitive for lead infection and CIED-IE with pooled sensitivity and specificity of 76% and 83%, respectively [37].

Figure 7.

Infected left ventricular assist device and driveline. There is abnormal 18F-FDG accumulation around the device (top) and driveline (bottom, arrows).

2.2.3 Prosthetic vascular graft infections

Although prosthetic vascular graft infections are infrequent, they are associated with high morbidity and sometimes, mortality. Underlying comorbidities increase risk of infection and infection-related complications, such as sepsis, enteric fistulae, spread of infection to other sites, and death [38].

18F-FDG accurately diagnoses prosthetic vascular graft infection, with sensitivity and specificity ranging from 88% to 100% [39, 40]. It is important to be cognizant of the fact that these grafts can incite a foreign-body inflammatory response that can lead to increased 18F-FDG uptake in the absence of infection. Familiarity with typical 18F-FDG uptake patterns associated with infection and foreign body reaction is important. Vascular graft infection generally presents as focal or heterogeneously increased 18F-FDG uptake that projects over the vessel on the CT component of the examination (Figure 8). In contrast, the aseptic foreign body reaction presents as linear, diffuse, and homogeneous uptake along the graft (Figure 9) [41, 42].

Figure 8.

Infected aortic endovascular stent. There is intense heterogeneous 18F-FDG uptake surrounding the vascular stent.

Figure 9.

Uninfected endovascular stent. There is faint homogeneous 18F-FDG uptake around this stent (arrows). Compare this pattern with that of the infected stent in Figure 8.

2.3 Sarcoidosis

Sarcoidosis is a multisystemic disease that most often affects the lungs and intrathoracic lymph nodes but can involve any organ in the body. The diagnosis is based on a combination of history, physical examination, radiologic and pathologic findings, and exclusion of other causes [43, 44].

18F-FDG, the molecular imaging study of choice for sarcoid, with an overall sensitivity of 89−100% is more sensitive than the ACE and soluble interleukin-2 receptor tests (Figure 10). Whole-body imaging facilitates identification of unsuspected disease sites and guides management in these patients [45, 46]. 18F-FDG is useful for monitoring treatment response. A decrease in 18F-FDG lesion avidity after the initiating treatment correlates with clinical improvement, while persistent activity identifies nonresponders [47, 48].

Figure 10.

Sarcoidosis. There is intense 18F-FDG uptake in multiple mediastinal lymph nodes, with patchy less intense uptake in both lungs, greater on the right.

Pulmonary parenchymal uptake of 18F-FDG uptake correlates with active pulmonary disease and predicts response to anti-inflammatory treatment [49]. 18F-FDG uptake correlates with the bronchoalveolar lavage fluid neutrophil count and may serve as a noninvasive prognostic tool [50].

In patients with pulmonary involvement, distinguishing between fibrosis and fibrosis with active inflammation is important because patients with active inflammation could benefit from a change in therapy. Published data suggest that 18F-FDG can facilitate the differentiation between pure fibrosis and fibrosis plus inflammation because pulmonary fibrotic changes do not demonstrate uptake while active lesions do. It is superior to high-resolution CT and serological evaluation for this purpose [50, 51].

2.4 Tuberculosis

Tuberculosis is the leading cause of infectious disease–related mortality worldwide. One-fourth of the world’s population is latently infected and 3–5% of these individuals develop active tuberculosis disease during their lifetime. The lungs are the most common site of involvement and pulmonary disease is present in more than 80% of cases. The most common sites of extrapulmonary disease are thoracic and cervical lymph nodes, spine, adrenal glands, meninges, and gastrointestinal and genitourinary tracts [52, 53]. Early, accurate diagnosis with prompt initiation of treatment is important to minimize morbidity and mortality and to reduce the likelihood of transmission. 18F-FDG is useful for identifying both pulmonary and extrapulmonary disease, measuring disease activity, identifying individuals with latent tuberculous infection at risk of developing an active infection, and monitoring response to treatment. In patients with active infection, there are two general patterns of 18F-FDG uptake. The lung pattern is associated with pulmonary tuberculosis. Mediastinal lymph nodes can be slightly enlarged and demonstrate moderate 18F-FDG uptake. The lymphatic pattern is associated with predominantly systemic, extra-thoracic disease. Mediastinal lymph nodes are larger and have higher 18F-FDG uptake than those in patients with the lung pattern. Immunocompetent patients tend to develop the lung pattern, while immunocompromised patients are more likely to develop the lymphatic pattern [54].

Lesion activity as measured by SUV correlates with disease activity. Using dual time-point imaging, it may be possible to distinguish active from inactive pulmonary tuberculomas. Active pulmonary tuberculomas have a higher SUV max at 1 and 2 hours and a greater increase in SUV max from early to late imaging compared to inactive tuberculomas [55]. 18F-FDG uptake can be present in clinically cured patients who do not go on to develop active disease. This may represent a post-treatment equilibrium in which the immune system prevents replicating bacilli from progressing to overt disease [56].

Identifying individuals with latent tuberculosis infection who are at risk of progressing to active infection is important because they should be treated. In one investigation, 18F-FDG showed infiltrates and/or fibrotic scars or active nodules in ten asymptomatic subjects with an initial negative screen for active disease. These subjects were significantly more likely to have 18F-FDG uptake within mediastinal lymph nodes compared to 25 subjects with either normal lung parenchyma or discrete small nodules [57].

18F-FDG can assess early treatment response when radiological features may remain unchanged, with consequent significant impact on patient management. In 28 subjects with multidrug-resistant disease, 18F-FDG-PET/CT performed 2 months into treatment was the best method for early prediction of treatment results and long-term outcomes [58].

In summary, 18F-FDG is valuable for staging tuberculosis, locating extrapulmonary disease, identifying patients with subclinical tuberculosis, and assessing early treatment response.

2.5 Fever of unknown origin

Fever, or pyrexia, of unknown origin (FUO) is a fever that exceeds 38.3°C (101°F) on several occasions, with more than 3 weeks' duration of illness, and a failure to obtain a diagnosis after an appropriate inpatient or outpatient workup. FUO is divided into four categories: classic (the most common), nosocomial, neutropenic, and HIV-associated. Causes of classic FUO are divided into five categories: infection, neoplasm, inflammation, miscellaneous, and undiagnosed. The relative frequencies of these categories vary with the historical period, geographic region, care setting (tertiary versus community), and patient population. The etiology of FUO is undiagnosed in up to 50% of patients [59].

The workup of a patient with FUO consists of several first-line investigations: history and physical examination, laboratory tests, chest x-ray, and echocardiography when endocarditis is suspected. When first-line investigations do not yield a diagnosis, second-line procedures, including CT, MRI, and molecular imaging studies, are performed. 67Ga and labeled leukocyte scintigraphy, at one time the mainstays of molecular imaging for FUO, have been replaced by 18F-FDG as the molecular imaging test of choice in this population (Figure 11). Abnormalities identified with 18F-FDG guide additional investigations that may yield a final diagnosis. A negative study excludes these conditions with a reasonable certainty, thereby avoiding unnecessary additional testing. A negative result is a good predictor of a favorable prognosis. Performed within the first 1−2 weeks in the FUO workup, 18F-FDG is cost-effective by obtaining a diagnosis sooner, reducing the number of expensive, potentially invasive, diagnostic procedures performed, and decreasing the number of patients without a final diagnosis [59].

Figure 11.

Vasculitis. There is diffuse 18F-FDG throughout the wall of the thoracic and abdominal aorta with extension into the subclavian and iliac arteries. 18F-FDG is very sensitive for detecting large vessel vasculitis, which is a well-recognized cause of fever of unknown origin.

18F-FDG contributes useful information in children with FUO. In one investigation, 19 (43%) of 44 scans were helpful by allowing focused evaluation in 9 cases and eliminating further workup in 10 cases [60]. In one of the largest pediatric studies to date, (n = 110) 18F-FDG PET/CT established a definite diagnosis in 62% and led to treatment modification in 53% [61]. 18F-FDG is helpful in children with terminal chronic liver failure and FUO during the pretransplantation period, as well as in immunocompromised children with fever [62, 63].

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3. Gallium-68 citrate

For nearly 50 years, 67Ga has been used for imaging infection. Now that gallium-68 citrate (68Ga) is available, investigators have studied the role of this agent in diagnosing infection [64]. In a pilot study, 68Ga accumulated in pulmonary and extra-pulmonary sites of disease in patients with tuberculosis was superior to CT for detecting extra-pulmonary disease. Not all pulmonary lesions concentrated 68Ga and the authors hypothesized that this radiopharmaceutical might be useful for differentiating active from inactive disease and for monitoring treatment response [65]. In another investigation of patients with tuberculosis, although more lesions overall were detected with 18F-FDG, brain lesions were better defined with 68Ga, presumably due to the lack of physiological brain uptake of this radiopharmaceutical [66].

The potential of 68Ga for diagnosing musculoskeletal infection also has been studied. In one investigation of 31 patients with suspected musculoskeletal infection, all 23 infections were detected. There were four false positive results all of which were due to tumor. Sensitivity, specificity, and accuracy were 100%, 76%, and 90%, respectively [67]. In a prospective investigation, 34 patients with clinically proven or suspected lower extremity PJI underwent 18F-FDG and 68Ga-citrate PET/CT. Sensitivity, specificity, and accuracy of 68Ga-citrate PET/CT and 18F-FDG PET/CT were 92%, 88%, and 91% and 100%, 38%, and 85%, respectively. The authors concluded that preliminary evidence suggests that 68Ga-citrate PET/CT potentially could be complementary to 18F-FDG PET/CT by facilitating the differentiation between infection and aseptic inflammation [68].

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4. Labeled leukocytes

Although 18F-FDG and 68Ga are useful in the diagnostic workup of patients with infectious diseases, they are not specific and accumulate in noninfectious conditions, including benign and malignant neoplasms, and various noninfectious inflammatory conditions. Considerable effort has been devoted to developing positron-emitting radiopharmaceuticals that are specific, or at least more specific for infection, than 18F-FDG and 68Ga.

4.1 18F-FDG labeled leukocytes

One of the earliest attempts at creating a more specific PET radiopharmaceutical for infection imaging was the development of an in vitro method for labeling autologous leukocytes with 18F-FDG [69, 70]. A recent meta-analysis indicates that 18F-FDG labeled leukocyte imaging accurately diagnoses infection [71]. Seven studies (n = 236) were included in the meta-analysis. Pooled sensitivity was 86.3% (95%CI: 75−92.9%) and pooled specificity was 92% (95% CI: 79.8−97.1%). The positive likelihood ratio was 6.6 (95% CI: 3.1−14.1) and the negative likelihood ratio was 0.2 (95% CI: 0.12−0.33).

In spite of these favorable results, 18F-FDG WBC has not been integrated into the routine diagnostic workup of infection. There are several reasons for this. Labeling efficiency is variable both in patients and normal volunteers, ranging from less than 25% to more than 95% [72, 73, 74, 75, 76, 77, 78]. This inconsistency makes it difficult to determine the quantity of 18F-FDG needed for labeling leukocytes. If a worst-case labeling efficiency scenario is assumed, that is, 35%, what happens if the labeling efficiency is 80%? Is the amount of activity reinfused is reduced accordingly? If so, will the number of labeled leukocytes reinfused be adequate to provide diagnostically useful data?

Stability of the 18F-FDG WBC label is another issue. In one investigation, leukocyte retention of 18F-FDG decreased from 39% to 44% at 90 minutes to 19% at 4 hours [75]. In an investigation of normal volunteers, mean leukocyte retention of 18F-FDG was 85% ± 4% at 1 hour, and 68% ± 7% at 4 hours [77]. In view of the degree of 18F-FDG elution, one has to question whether imaging findings reflect accumulation of 18F-FDG WBC, 18F-FDG, or a combination.

The 110 minute physical half-life of fluorine-18 is a significant disadvantage. The time needed for in vitro labeling, up to 3 hours, needs to be accounted for when determining the amount of activity used to label the leukocytes. The short half-life makes it impractical for labeling to be performed off-site, which is a significant limitation in the United States where the vast majority of these labelings are performed at outside radiopharmacies. In indolent, low-grade, infections, leukocyte accumulation is slow, and imaging at later time points (e.g., 24 hours) may be necessary. The short half-life of fluorine-18 precludes imaging more than 4–5 hours after reinfusion of labeled cells. For all of these reasons, it is unlikely that 18F-FDG-labeled leukocyte imaging will ever become part of mainstream clinical nuclear medicine.

4.2 Copper-64 labeled leukocytes

64Cu labeling of leukocytes also has been investigated. In 10 normal volunteers, the labeling efficiency, cell viability, and stability of 64Cu labeled leukocytes were compared with those of 111In labeled leukocytes and 18F-FDG labeled leukocytes [77]. The mean labeling efficiency for 64Cu labeled leukocytes, 87% ± 4%, was nearly identical to that of 111In labeled leukocytes 86% ± 4%. Leukocyte viability was the same for both radiolabels at 1 hour, 99% ± 1%, but was significantly higher for 64Cu labeled leukocytes than for 111In labeled leukocytes at 3 hours (98% vs. 96%, respectively) and at 24 hours (61% vs. 48%, respectively). Label stability was significantly higher for 111In labeled leukocytes at 1, 2, 3, 4, and 24 hours (94%, 93%, 92%, 91%, and 88%, respectively) than for 64Cu labeled leukocytes (91%, 89%, 88%, 86%, and 79%) and 18F-FDG WBC (85% ± 4%, 81% ± 4%,76% ± 4%, and 68% ± 7%). Unfortunately, the labeling procedure required the use of two chelating agents: tropolone to allow the 64Cu ion to enter the cell, and quin-MF/AM, to prevent elution. This complex, time-consuming procedure, which requires skilled personnel, is not well suited to routine clinical use.

Chitosan nanoparticles also have been used to label human leukocytes with 64Cu. The labeling efficiency was only about 26% and more than 90% of the activity had eluted from the leukocytes at 2 hours [79].

4.3 Zirconium-89 labeled leukocytes

89Zr, with a half-life of 78.4 hours, has also been used to label leukocytes in vitro. In one investigation, chitosan nanoparticles were used to label human leukocytes with 89Zr. Labeling efficiency was 76.8%. Cell viability at the completion of labeling was 61%; 28.4% of the intracellular activity had eluted at 2 hours, 35.2% at 4 hours, and 53.3% at 24 hours. The entire labeling process took nearly 6 hours to complete. In this investigation, only 61% of the labeled leukocytes were viable.

Recent investigations are more promising. In one study, in vitro labeling of human leukocytes with 89Zr-oxine was compared to labeling with 111In-oxine [80]. Labeling efficiency for 89Zr labeled leukocytes was 48.7% vs. 89.1% (P < 0.0001) for 111In labeled leukocytes. However, there were no significant differences between 89Zr labeled leukocytes and 111In labeled leukocytes with respect to elution of activity or cell viability. Another group obtained similar results when using 89Zr-oxinate4 to label human leukocytes [81]. These results are encouraging, but in vivo investigations of 89Zr labeled leukocytes to diagnose infection are lacking.

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5. Infection-specific agents

5.1 Iodine-124 fialuridine

The radioiodinated thymidine analog fialuridine (FIAU) was developed for reporter genes, for cells that were transfected with herpes simplex virus thymidine kinase (TK). This enzyme transfers a phosphate group from ATP to pyrimidine deoxynucleoside. The lipophilic agent diffuses into the cell where it is trapped with the TK activity [82]. FIAU is also phosphorylated by endogenous bacterial TK. In a pilot investigation, 124I-FIAU PET/CT successfully detected musculoskeletal infection in seven patients and was negative in one healthy control [83]. Results of subsequent investigations of 124I-FIAU for diagnosing musculoskeletal infection were less satisfactory. In 19 subjects with suspected lower extremity PJI, image quality was suboptimal because of metal artifact and high nonspecific muscle uptake [84]. In an investigation of 124I FIAU for diagnosing foot osteomyelitis in diabetics the study was terminated because of a lack of correlation between 124I FIAU uptake and bone biopsy results [85].

5.2 Fluorine-18 fluorodeoxysorbitol

Sorbitol, a sugar alcohol, is a metabolic substrate for Enterobacteriaceae, the largest group of Gram-negative bacterial pathogens in humans. Sorbitol is selectively taken up by bacteria via surface transporters, phosphorylated, and further metabolized [86]. The radiolabeled sorbitol analog, 18F-FDS rapidly and selectively accumulates in Enterobacteriaceae. In a murine myositis model, 18F-FDS PET rapidly differentiated infection from sterile inflammation [87]. 18F-FDS was determined to be safe and well tolerated after a single intravenous dose was injected into healthy human volunteers to assess biodistribution and radiation dosimetry [88].

In a prospective investigation of 26 patients, 18F-FDS PET/CT was safe, rapidly localized Enterobacterales infections and differentiated them from sterile inflammation and tumor. Follow-up imaging in the same patients performed for monitoring antibiotic treatment demonstrated decreased uptake correlating with clinical improvement [89].

5.3 Antimicrobial peptides

Antimicrobial peptides (AMPs) bind to the bacterial cell membrane. Their expression may be constant or induced by contact with microbes. They also may be transported to sites of infection by leukocytes [90]. Radiolabeled synthetic fragments of ubiquicidin, a naturally occurring human AMP that targets bacteria, possess the ability to differentiate infection from sterile inflammation and have shown potential for monitoring treatment in staphylococcus aureus infections [91, 92, 93].

Although 99mTc labeled AMPS have been used in most investigations, preclinical data indicate that 68Ga labeled AMPS can be used to detect and localize infection [94]. 68Ga-DOTA-TBIA101 successfully detected E. coli-infected muscle tissue in mice. Normalization of the infected thigh muscle to reference tissue showed a ratio of 3.0 ± 0.8 and a ratio of 2.3 ± 0.6 compared to the identical healthy [95]. Although these results are encouraging, at the present time human data are too few to draw any conclusions about the clinical utility of these agents.

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6. Conclusions

18F-FDG is extremely useful in the diagnostic workup of patients suspected of having infection. It has emerged as the molecular imaging test of choice for spondylodiscitis, FUO in both adults and children, sarcoid, and vasculitis. This test is also valuable in the diagnostic workup of patients with diabetic foot and cardiovascular infections. The most significant limitation of 18F-FDG is a lack of specificity. Investigators have sought to capitalize on the advantages of PET over single photon emitting radiopharmaceuticals, by developing PET radiopharmaceuticals that are more specific for infection. Early efforts focused on in vitro labeling of leukocytes with PET radiopharmaceuticals but for a variety of reasons, these agents have not entered the clinical arena, nor is it likely that they will. Initial results with 124I-FIAU were encouraging, but subsequent data dampened the enthusiasm for this agent. Based on preliminary data, 18F-FDS and 68Ga labeled siderophores and AMPs show promise as infection-specific agents. However, clinical trials are needed to establish their value.

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Conflict of interest

The author declares no conflict of interest.

References

  1. 1. Palestro CJ. Molecular imaging of infection: the first 50 years. Seminars in Nuclear Medicine. 2020;50:23-34. DOI: 10.1053/j.semnuclmed.2019.10.002
  2. 2. Zhuang H, Alavi A. 18-fluorodeoxyglucose positron emission tomographic imaging in the detection and monitoring of infection and inflammation. Seminars in Nuclear Medicine. 2002;32:47-59. DOI: 10.1053/snuc.2002.29278
  3. 3. Meller J, Sahlmann CO, Scheel AK. 18F-FDG PET and PET/CT in fever of unknown origin. Journal of Nuclear Medicine. 2007;48:35-45
  4. 4. Love C, Tomas MB, Tronco GG, Palestro CJ. FDG PET of infection and inflammation. Radiographics. 2005;25:1357-1368. DOI: 10.1148/rg.255045122
  5. 5. Palestro CJ. FDG PET in musculoskeletal infection. Seminars in Nuclear Medicine. 2013;43:367-376. DOI: 10.1053/j.semnuclmed.2013.04.006
  6. 6. Wang GL, Zhao K, Liu ZF, Dong MJ, Yang SY. A meta-analysis of fluorodeoxyglucose-positron emission tomography versus scintigraphy in the evaluation of suspected osteomyelitis. Nuclear Medicine Communications. 2011;32:1134-1142. DOI: 10.1097/MNM.0b013e32834b455c
  7. 7. Termaat MF, Raijmakers PG, Scholten HJ, et al. The accuracy of diagnostic imaging for the assessment of chronic osteomyelitis: a systematic review and meta-analysis. The Journal of Bone and Joint Surgery. American Volume. 2005;87:2464-2471. DOI: 10.2106/JBJS.D.02691
  8. 8. Prodromou ML, Ziakas PD, Poulou LS, Karsaliakos P, Thanos L, Mylonakis E. FDG PET is a robust tool for the diagnosis of spondylodiscitis: a meta-analysis of diagnostic data. Clinical Nuclear Medicine. 2014;39:330-335. DOI: 10.1097/RLU.0000000000000336
  9. 9. Treglia G, Pascale M, Lazzeri E, van der Bruggen W, Delgado Bolton RC, Glaudemans AWJM. Diagnostic performance of 18F-FDG PET/CT in patients with spinal infection: a systematic review and a bivariate meta-analysis. European Journal of Nuclear Medicine and Molecular Imaging. 2020;47:1287-1301. DOI: 10.1007/s00259-019-04571-6
  10. 10. Gratz S, Dorner J, Fischer U, et al. 18F-FDG hybrid PET in patients with suspected spondylitis. European Journal of Nuclear Medicine and Molecular Imaging. 2002;29:516-524
  11. 11. Fuster D, Solà O, Soriano A, et al. A prospective study comparing whole-body FDG PET/CT to combined planar bone scan with 67Ga SPECT/CT in the diagnosis of spondylodiskitis. Clinical Nuclear Medicine. 2012;37:827-832. DOI: 10.1097/RLU.0b013e318262ae6c
  12. 12. Frenkel Rutenberg T, Baruch Y, Ohana N, et al. The role of 18F-fluorodeoxyglucose positron-emission tomography/computed tomography in the diagnosis of postoperative hardware-related spinal Infections. The Israel Medical Association Journal. 2019;21(8):532-537
  13. 13. Skanjeti A, Penna D, Douroukas A, et al. PET in the clinical work-up of patients with spondylodiscitis: a new tool for the clinician? The Quarterly Journal of Nuclear Medicine and Molecular Imaging. 2012;56:569-576
  14. 14. Kim SJ, Kim IJ, Suh KT, et al. Prediction of residual disease of spine infection using F-18 FDG PET/CT. Spine. 2009;34:2424-2430. DOI: 10.1097/BRS.0b013e3181b1fd33
  15. 15. Nanni C, Boriani L, Salvadori C, et al. FDG PET/CT is useful for the interim evaluation of response to therapy in patients affected by haematogenous spondylodiscitis. European Journal of Nuclear Medicine and Molecular Imaging. 2012;39:1538-1544. DOI: 10.1007/s00259-012-2179-8
  16. 16. Ioannou S, Chatziioannou S, Pneumaticos SG, Zormpala A, Sipsas NV. Fluorine-18 fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography scan contributes to the diagnosis and management of brucellar spondylodiskitis. BMC Infectious Diseases. 2013;13:73. DOI: 10.1186/1471-2334-13-73
  17. 17. Righi E, Carnelutti A, Muser D, et al. Incremental value of FDG-PET/CT to monitor treatment response in infectious spondylodiscitis. Skeletal Radiology. 2020;49:903-912. DOI: 10.1007/s00256-019-03328-4
  18. 18. Riccio SA, Chu AK, Rabin HR, Kloiber R. Fluorodeoxyglucose positron emission tomography/computed tomography interpretation criteria for assessment of antibiotic treatment response in pyogenic spine infection. Canadian Association of Radiologists Journal. 2015;66:145-152. DOI: 10.1016/j.carj.2014.08.004
  19. 19. Yu GJ, Koslowsky IL, Riccio SA, Chu AKM, Rabin HR, Kloiber R. Diagnostic challenges in pyogenic spinal infection: an expanded role for FDG-PET/CT. European Journal of Clinical Microbiology & Infectious Diseases. 2018;37:501-509. DOI: 10.1007/s10096-018-3197-7
  20. 20. Palestro CJ, Love C. Nuclear medicine and diabetic foot infections. Seminars in Nuclear Medicine. 2009;39:52-65. DOI: 10.1053/j.semnuclmed.2008.08.006
  21. 21. Treglia G, Sadeghi R, Annunziata S, et al. Diagnostic performance of fluorine-18-fluorodeoxyglucose positron emission tomography for the diagnosis of osteomyelitis related to diabetic foot: a systematic review and a meta-analysis. Foot (Edinburgh, Scotland). 2013;23:140-148. DOI: 10.1016/j.foot.2013.07.002
  22. 22. Lauri C, Tamminga M, Glaudemans AWJM, et al. Detection of osteomyelitis in the diabetic foot by imaging techniques: a systematic review and meta-analysis comparing MRI, white blood cell scintigraphy, and FDG-PET. Diabetes Care. 2017;40:1111-1120. DOI: 10.2337/dc17-0532
  23. 23. Jin H, Yuan L, Li C, Kan Y, Hao R, Yang J. Diagnostic performance of FDG PET or PET/CT in prosthetic infection after arthroplasty: a meta-analysis. The Quarterly Journal of Nuclear Medicine and Molecular Imaging. 2014;58:85-93
  24. 24. Kwee TC, Kwee RM, Alavi A. FDG-PET for diagnosing prosthetic joint infection: Systematic review and metaanalysis. European Journal of Nuclear Medicine and Molecular Imaging. 2008;35:2122-2132. DOI: 10.1007/s00259-008-0887-x
  25. 25. Palestro CJ. Molecular Imaging of Periprosthetic Joint Infections. Seminars in Nuclear Medicine. 2023;52:167-174. DOI: 10.1053/j.semnuclmed.2022.11.004
  26. 26. Pinski JM, Chen AF, Estok DM, Kavolus JJ. Nuclear medicine scans in total joint replacement. Journal of Bone and Joint Surgery. 2011;103:359-372. DOI: 10.2106/JBJS.20.00301
  27. 27. Falstie-Jensen T, Lange J, Daugaard H, et al. 18F FDG-PET/CT has poor diagnostic accuracy in diagnosing shoulder PJI. European Journal of Nuclear Medicine and Molecular Imaging. 2019;46:2013-2022. DOI: 10.1007/s00259-019-04381-w
  28. 28. Holland TL, Baddour LM, Bayer AS, Hoen B, Miro JM, Fowler VG Jr. Infective endocarditis. Nature Reviews. Disease Primers. 2016;2:16059. DOI: 10.1038/nrdp.2016.59
  29. 29. Erba PA, Conti U, Lazzeri E, et al. Added value of 99mTc-HMPAO-labeled leukocyte SPECT/CT in the characterization and management of patients with infectious endocarditis. Journal of Nuclear Medicine. 2012;53:1235-1243. DOI: 10.2967/jnumed.111.099424
  30. 30. Yan J, Zhang C, Niu Y, et al. The role of 18F-FDG PET/CT in infectious endocarditis: a systematic review and meta-analysis. International Journal of Clinical Pharmacology and Therapeutics. 2016;54:337-342. DOI: 10.5414/CP202569
  31. 31. Rouzet F, Chequer R, Benali K, et al. Respective performance of 18F-FDG PET and radiolabeled leukocyte scintigraphy for the diagnosis of prosthetic valve endocarditis. Journal of Nuclear Medicine. 2014;55:1980-1985. DOI: 10.2967/jnumed.114.141895
  32. 32. Baddour LM, Epstein AE, Erickson CC, et al. Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association. Circulation. 2010;121:458-477. DOI: 10.1161/CIRCULATIONAHA.109.192665
  33. 33. Pizzi MN, Roque A, Fernández-Hidalgo N, et al. Improving the diagnosis of infective endocarditis in prosthetic valves and intracardiac devices with 18F-Fluordeoxyglucose positron emission tomography/computed tomography angiography: initial results at an infective endocarditis referral center. Circulation. 2015;132:1113-1126. DOI: 10.1161/CIRCULATIONAHA.115.015316
  34. 34. Bensimhon L, Lavergne T, Hugonnet F, et al. Whole body [(18) F]fluorodeoxyglucose positron emission tomography imaging for the diagnosis of pacemaker or implantable cardioverter defibrillator infection: a preliminary prospective study. Clinical Microbiology and Infection. 2011;17:836-844. DOI: 10.1111/j.1469-0691.2010.03312.x
  35. 35. Sarrazin JF, Philippon F, Tessier M, et al. Usefulness of fluorine-18 positron emission tomography/computed tomography for identification of cardiovascular implantable electronic device infections. Journal of the American College of Cardiology. 2012;59:1616-1625. DOI: 10.1016/j.jacc.2011.11.059
  36. 36. Dell'Aquila AM, Mastrobuoni S, Alles S, et al. Contributory role of fluorine 18-fluorodeoxyglucose positron emission tomography/computed tomography in the diagnosis and clinical management of infections in patients supported with a continuous-flow left ventricular assist device. The Annals of Thoracic Surgery. 2016;101:87-94. DOI: 10.1016/j.athoracsur.2015.06.066
  37. 37. Mahmood M, Kendi AT, Farid S, et al. Role of 18F-FDG PET/CT in the diagnosis of cardiovascular implantable electronic device infections: a meta-analysis. Journal of Nuclear Cardiology. 2019;26:958-970. DOI: 10.1007/s12350-017-1063-0
  38. 38. Wilson WR, Bower TC, Creager MA, et al. Vascular graft infections, mycotic aneurysms, and endovascular infections: a scientific statement from the American Heart Association. Circulation. 2016;134:e412-e460. DOI: 10.1161/CIR.0000000000000457
  39. 39. Keidar Z, Engel A, Hoffman A, Israel O, Nitecki S. Prosthetic vascular graft infection: the role of 18F-FDG PET/CT. Journal of Nuclear Medicine. 2007;48:1230-1126. DOI: 10.2967/jnumed.107.040253
  40. 40. Sah BR, Husmann L, Mayer D, et al. VASGRA Cohort. Diagnostic performance of 18F-FDG-PET/CT in vascular graft infections. European Journal of Vascular and Endovascular Surgery. 2015;49:455-464. DOI: 10.1016/j.ejvs.2014.12.024
  41. 41. Keidar Z, Pirmisashvili N, Leiderman M, Nitecki S, Israel O. 18F-FDG uptake in noninfected prosthetic vascular grafts: incidence, patterns, and changes over time. Journal of Nuclear Medicine. 2014;55:392-395. DOI: 10.2967/jnumed.113.128173
  42. 42. Saleem BR, Pol RA, Slart RH, Reijnen MM, Zeebregts CJ. 18F-Fluorodeoxyglucose positron emission tomography/CT scanning in diagnosing vascular prosthetic graft infection. BioMed Research International. 2014;2014:471971. DOI: 10.1155/2014/471971
  43. 43. Llanos O, Hamzeh N. Sarcoidosis. The Medical Clinics of North America. 2019;103:527-534. DOI: 10.1016/j.mcna.2018.12.011
  44. 44. Brown F, Modi P, Tanner LS. Lofgren syndrome. 2020 Aug 8. In: StatPearls. StatPearls Publishing; 2022. Bookshelf ID: NBK482315
  45. 45. Keijsers RGM, Grutters JC. In which patients with sarcoidosis is FDG PET/CT indicated? Journal of Clinical Medicine. 2020;9:890. DOI: 10.3390/jcm9030890
  46. 46. Akaike G, Itani M, Shah H, et al. PET/CT in the diagnosis and workup of sarcoidosis: focus on atypical manifestations. Radiographics. 2018;38:1536-1549. DOI: 10.1148/rg.2018180053
  47. 47. Sobic-Saranovic D, Grozdic I, Videnovic-Ivanov J, et al. The utility of 18F-FDG PET/CT for diagnosis and adjustment of therapy in patients with active chronic sarcoidosis. Journal of Nuclear Medicine. 2012;53:1543-1549. DOI: 10.2967/jnumed.112.104380
  48. 48. Maturu VN, Rayamajhi SJ, Agarwal R, Aggarwal AN, Gupta D, Mittal BR. Role of serial F-18 FDG PET/CT scans in assessing treatment response and predicting relapses in patients with symptomatic sarcoidosis. Sarcoidosis, Vasculitis, and Diffuse Lung Diseases. 2016;33:372-380
  49. 49. Keijsers RG, Verzijlbergen JF, van Diepen DM, van den Bosch JM, Grutters JC. 18F-FDG PET in sarcoidosis: an observational study in 12 patients treated with infliximab. Sarcoidosis, Vasculitis, and Diffuse Lung Diseases. 2008;25:143-149
  50. 50. Guleria R, Jyothidasan A, Madan K, et al. Utility of FDG-PET-CT scanning in assessing the extent of disease activity and response to treatment in sarcoidosis. Lung India. 2014;31:323-330. DOI: 10.4103/0970-2113.142092
  51. 51. Mostard RL, Vöö S, van Kroonenburgh MJ, et al. Inflammatory activity assessment by F18 FDG-PET/CT in persistent symptomatic sarcoidosis. Respiratory Medicine. 2011;105:1917-1924. DOI: 10.1016/j.rmed.2011.08.012
  52. 52. Yu WY, Lu PX, Assadi M, et al. Updates on 18F-FDG-PET/CT as a clinical tool for tuberculosis evaluation and therapeutic monitoring. Quantitative Imaging in Medicine and Surgery. 2019;9:1132-1146. DOI: 10.21037/qims.2019.05.24
  53. 53. Ankrah AO, Glaudemans AWJM, Maes A, et al. Tuberculosis. Seminars in Nuclear Medicine. 2018;48:108-130. DOI: 10.1053/j.semnuclmed.2017.10.005
  54. 54. Soussan M, Brillet PY, Mekinian A, et al. Patterns of pulmonary tuberculosis on FDG-PET/CT. European Journal of Radiology. 2012;81:2872-2286. DOI: 10.1016/j.ejrad.2011.09.002
  55. 55. Kim IJ, Lee JS, Kim SJ, et al. Double-phase 18F-FDG PET-CT for determination of pulmonary tuberculoma activity. European Journal of Nuclear Medicine and Molecular Imaging. 2008;35:808-814. DOI: 10.1007/s00259-007-0585-0
  56. 56. Malherbe ST, Shenai S, Ronacher K, et al. Persisting positron emission tomography lesion activity and Mycobacterium tuberculosis mRNA after tuberculosis cure. Nature Medicine. 2016;22:1094-1100. DOI: 10.1038/nm.4177
  57. 57. Esmail H, Lai RP, Lesosky M, et al. Characterization of progressive HIV-associated tuberculosis using 2-deoxy-2-[18F]fluoro-D-glucose positron emission and computed tomography. Nature Medicine. 2016;22:1090-1093. DOI: 10.1038/nm.4161
  58. 58. Chen RY, Dodd LE, Lee M, et al. PET/CT imaging correlates with treatment outcome in patients with multidrug-resistant tuberculosis. Science Translational Medicine. 2014;6:265ra166. DOI: 10.1126/scitranslmed.3009501
  59. 59. Palestro CJ, Brandon D, Dibble EH, Keidar Z, Kwak J. FDG PET in evaluation of patients with fever of unknown origin: AJR Expert Panel Narrative Review. AJR. American Journal of Roentgenology. DOI: 10.2214/AJR.22.28726 [Online ahead of print]
  60. 60. Jasper N, Dabritz J, Frosch M, Loeffler M, Weckesser M, Foell D. Diagnostic value of 18F-FDG PET/CT in children with fever of unknown origin or unexplained signs of inflammation. European Journal of Nuclear Medicine and Molecular Imaging. 2010;37:136-145. DOI: 10.1007/s00259-009-1185-y
  61. 61. Pijl JP, Kwee TC, Legger GE, et al. Role of FDG-PET/CT in children with fever of unknown origin. European Journal of Nuclear Medicine and Molecular Imaging. 2020;47:1596-1604. DOI: 10.1007/s00259-020-04707-z
  62. 62. Sturm E, Rings EH, Scholvinck EH, Gouw AS, Porte RJ, Pruim J. Fluordeoxyglucose positron emission tomography contributes to management of pediatric liver transplantation candidates with fever of unknown origin. Liver Transplantation. 2006;12:1698-1704. DOI: 10.1002/lt.20922
  63. 63. Wang SS, Mechinaud F, Thursky K, Cain T, Lau E, Haeusler GM. The clinical utility of fluorodeoxyglucose positron emission tomography for investigation of fever in immunocompromised children. Journal of Paediatrics and Child Health. 2018;54:487-492. DOI: doi.org/10.1111/jpc.13809
  64. 64. Kumar V, Boddeti DK, Evans SG, Angelides S. 68Ga-citrate-PET for diagnostic imaging of infection in rats and for intra-abdominal infection in a patient. Current Radiopharmaceuticals. 2012;5:71-75. DOI: 10.2174/1874471011205010071
  65. 65. Vorster M, Maes A, Van de Wiele C, Sathekge MM. 68Ga-citrate PET/CT in tuberculosis: a pilot study. The Quarterly Journal of Nuclear Medicine and Molecular Imaging. 2019;63:48-55. DOI: 10.23736/S1824-4785.16.02680-7
  66. 66. Ankrah AO, Lawal IO, Boshomane TMG, et al. Comparison of Fluorine(18)-fluorodeoxyglucose and Gallium(68)-citrate PET/CT in patients with tuberculosis. Nuklearmedizin. 2019;58:371-378. DOI: 10.1055/a-1000-6951
  67. 67. Nanni C, Errani C, Boriani L, et al. 68Ga-Citrate PET/CT for evaluating patients with infections of the bone: preliminary results. Journal of Nuclear Medicine. 2010;51:1932-1936. DOI: 10.2967/jnumed.110.080184
  68. 68. Tseng JR, Chang YH, Yang LY, et al. Potential usefulness of 68Ga-citrate PET/CT in detecting infected lower limb prostheses. EJNMMI Research. 2019;9(1):2. DOI: 10.1186/s13550-018-0468-3
  69. 69. Forstrom LA, Mullan BP, Hung JC, Lowe VJ, Thorson LM. 18F-FDG labelling of human leukocytes. Nuclear Medicine Communications. 2000;21:691-694. DOI: 10.1097/00006231-200007000-00014
  70. 70. Forstrom LA, Dunn WL, Mullan BP, Hung JC, Lowe VJ, Thorson LM. Biodistribution and dosimetry of [(18)F]fluorodeoxyglucose labelled leukocytes in normal human subjects. Nuclear Medicine Communications. 2002;23:721-725. DOI: 10.1097/00006231-200208000-00004
  71. 71. Meyer M, Testart N, Jreige M, et al. Diagnostic performance of PET or PET/CT using 18F-FDG labeled white blood cells in infectious diseases: a systematic review and a bivariate meta-analysis. Diagnostics (Basel). 2019;9:60. DOI: 10.3390/diagnostics9020060
  72. 72. Aksoy SY, Asa S, Ozhan M, et al. FDG and FDG-labelled leucocyte PET/CT in the imaging of prosthetic joint infection. European Journal of Nuclear Medicine and Molecular Imaging. 2014;41:556-564. DOI: 10.1007/s00259-013-2597-2
  73. 73. Bhattacharya A, Kochhar R, Sharma S, et al. PET/CT with 18F-FDG-labeled autologous leukocytes for the diagnosis of infected fluid collections in acute pancreatitis. Journal of Nuclear Medicine. 2014;55:1267-1272. DOI: 10.2967/jnumed.114.137232
  74. 74. Dumarey N, Egrise D, Blocklet D, et al. Imaging infection with 18F-FDG-labeled leukocyte PET/CT: initial experience in 21 patients. Journal of Nuclear Medicine. 2006;47:625-632
  75. 75. Pellegrino D, Bonab AA, Dragotakes SC, Pitman JT, Mariani G, Carter EA. 2005. Inflammation and infection: imaging properties of 18F-FDG-labeled white blood cells versus 18F-FDG. Journal of Nuclear Medicine. 2005;46:1522-1530
  76. 76. Rini JN, Bhargava KK, Tronco GG, et al. PET with FDG-labeled leukocytes versus scintigraphy with 111In-oxine-labeled leukocytes for detection of infection. Radiology. 2006;238:978-987. DOI: 10.1148/radiol.2382041993
  77. 77. Bhargava KK, Gupta RK, Nichols KJ, Palestro CJ. In vitro human leukocyte labeling with (64)Cu: an intraindividual comparison with (111)In-oxine and (18)F-FDG. Nuclear Medicine and Biology. 2009;36:545-549. DOI: 10.1016/j.nucmedbio.2009.03.001
  78. 78. Lafont P, Morelec I, Fraysse M, et al. 18F-FDG labelled leukocytes in vitro functional tests: viability, chemotaxis and phagocytosis assays. The Open Nuclear Medicine Journal. 2011;3:25-29. DOI: 10.2174/1876388X01103010025
  79. 79. Fairclough M, Prenant C, Ellis B, et al. A new technique for the radiolabelling of mixed leukocytes with zirconium-89 for inflammation imaging with positron emission tomography. Journal of Labelled Compounds and Radiopharmaceuticals. 2016;59:270-276. DOI: 10.1002/jlcr.3392
  80. 80. Man F, Khan AA, Carrascal-Miniño A, Blower PJ, TM de Rosales R. A kit formulation for the preparation of [89Zr]Zr(oxinate)4 for PET cell tracking: white blood cell labelling and comparison with [111In]In(oxinate)3. Nuclear Medicine and Biology. 2020;90-91:31-40. DOI: 10.1016/j.nucmedbio.2020.09.002
  81. 81. Massicano AVF, Bartels JL, Jeffers CD, et al. Production of [89 Zr]Oxinate4 and cell radiolabeling for human use. Journal of Labelled Compounds and Radiopharmaceuticals. 2021;64:209-216. DOI: 10.1002/jlcr.3901
  82. 82. Boerman OC, Laverman P, Oyen WJ. FIAU: from reporter gene imaging to imaging of bacterial proliferation. American Journal of Nuclear Medicine and Molecular Imaging. 2012;2:271-272
  83. 83. Diaz LA, Foss CA, Thornton K, et al. Imaging of musculoskeletal bacterial infections by [124I]FIAU-PET/CT. PLoS One. 2007;10:e1007. DOI: 10.1371/journal.pone.0001007
  84. 84. Zhang XM, Zhang HH, McLeroth P, et al. [124I]FIAU: Human dosimetry and infection imaging in patients with suspected prosthetic joint infection. Nuclear Medicine and Biology. 2016;43:273-279. DOI: 10.1016/j.nucmedbio.2016.01.004
  85. 85. [124I]FIAU-PET/CT scanning in diagnosing osteomyelitis in patients with diabetic foot. Available from: infection.clinicaltrials.gov/ct2/show/NCT01764919. Updated 6 April 2016. [Accessed: 14 February 2023]
  86. 86. Lengeler J. Nature and properties of hexitol transport systems in Escherichia coli. Journal of Bacteriology. 1975;124:39-47. DOI: 10.1128/jb.124.1.39-47.1975
  87. 87. Weinstein EA, Ordonez AA, DeMarco VP, et al. Imaging Enterobacteriaceae infection in vivo with 18F-fluorodeoxysorbitol positron emission tomography. Science Translational Medicine. 2014;6(259):259ra146. DOI: 10.1126/scitranslmed.3009815
  88. 88. Zhu W, Yao S, Xing H, et al. Biodistribution and radiation dosimetry of the enterobacteriaceae-specific imaging probe [18F]Fluorodeoxysorbitol determined by PET/CT in healthy human volunteers. Molecular Imaging and Biology. 2016;18:782-787. DOI: 10.1007/s11307-016-0946-9
  89. 89. Ordonez AA, Wintaco LM, Mota F, et al. Imaging Enterobacterales infections in patients using pathogen-specific positron emission tomography. Science Translational Medicine. 2021, 2021;13(589):eabe9805. DOI: 10.1126/scitranslmed.abe9805
  90. 90. Lupetti A, Pauwels EKJ, Nibbering PH, Welling MM. 99mTc-antimicrobial peptides: promising candidates for infection imaging. The Quarterly Journal of Nuclear Medicine. 2003;47:238-245
  91. 91. Lupetti A, Welling MM, Mazzi U, Nibbering PH, Pauwels EKJ. Technetium-99m labelled fluconazole and antimicrobial peptides for imaging of Candida albicans and Aspergillus fumigatus infections. European Journal of Nuclear Medicine and Molecular Imaging. 2002;29:674-679. DOI: 10.1007/s00259-001-0760-7
  92. 92. Sarda-Mantel L, Saleh-Mghir A, Welling MM, et al. Evaluation of 99mTc-UBI 29-41 scintigraphy for specific detection of experimental Staphylococcus aureus prosthetic joint infections. European Journal of Nuclear Medicine and Molecular Imaging. 2007;34:1302-1309. DOI: 10.1007/s00259-007-0368-7
  93. 93. Meléndez-Alafort L, Rodríguez-Cortés J, Ferro-Flores G, et al. Biokinetics of (99m)Tc-UBI 29-41 in humans. Nuclear Medicine and Biology. 2004;31:373-379. DOI: 10.1016/j.nucmedbio.2003.10.005
  94. 94. Ebenhan T, Chadwick N, Sathekge MM, et al. Peptide synthesis, characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infection imaging with PET/CT. Nuclear Medicine and Biology. 2014;41:390-400. DOI: 10.1016/j.nucmedbio.2014.02.001
  95. 95. Mokaleng BB, Ebenhan T, Ramesh S, et al. Synthesis, 68Ga-radiolabeling, and preliminary in vivo assessment of a depsipeptide-derived compound as a potential PET/CT infection imaging agent. BioMed Research International. 2015;2015:284354. DOI: 10.1155/2015/284354

Written By

Christopher J. Palestro

Submitted: 19 February 2023 Reviewed: 21 February 2023 Published: 13 April 2023

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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