Keywords

7.1 Introduction

2-[18F]fluoro-2-deoxy-d-glucose (2-[18F]FDG) positron emission tomography (PET) has impacted the staging, restaging, and assessment of the therapeutic effect in a variety of malignancies. However, 2-[18F]FDG uptake is not specific for malignancies, and nonmalignant lesions such as infection, inflammation, granulomatous diseases, and autoimmune diseases with increased glycolysis can be visualized with 2-[18F]FDG PET. Currently, 2-[18F]FDG PET provides outstanding performance for the diagnosis of several infectious and inflammatory diseases and monitoring of response to therapy. This chapter describes the roles and limitations of 2-[18F]FDG PET and 2-[18F]FDG PET/computed tomography (CT) in the field of infectious and inflammatory diseases and adds some valuable knowledge about 2-[18F]FDG PET for the assessment of autoimmune diseases.

7.2 Mechanism of 2-[18F]FDG Uptake in Malignant and Inflammatory Cells

2-[18F]FDG is a glucose analog, which follows the same physiological processes as glucose, being taken up through cell surface glucose transporters and subsequently phosphorylated by the hexokinase enzyme to 2-[18F]FDG-6 phosphate, which is not metabolized further and remains trapped inside the cell. The degree of cellular 2-[18F]FDG uptake is related to the cellular metabolic rate and the number of glucose transporters [1,2,3]. Increased 2-[18F]FDG uptake in tumors is generally due to an increased number of glucose transporters in malignant cells. 2-[18F]FDG PET/CT has played an important role in staging, restaging, and evaluation of the therapeutic effect in a variety of malignancies.

Multiple mechanistic similarities in underlying metabolic pathways have been demonstrated between inflammatory and malignant cells [4, 5]. Inflammation can be broadly divided into three phases: (1) early vascular phase, (2) acute cellular phase, and (3) late cellular/healing phases. The earliest phase of inflammation shows tissue hyperemia, enhanced vascular permeability, and release of inflammatory mediators. The increase in tissue perfusion results in greater 2-[18F]FDG delivery to the affected sites [6, 7]. The second stage is that of active cell recruitment, migration, and proliferation at the site of inflammation. In this stage, glycolytic pathways are enhanced through the release of a multitude of cytokines, followed by upregulation of glucose transporter-1 (GLUT-1) and GLUT-3 and an increase in hexokinase activity [2, 4, 5, 8]. Hypoxia and toll-like-receptor activation are also influential factors that lead to the activation of this process [5]. Finally, in the transition from acute to chronic inflammation, the cellular environment changes from polymorphonuclear leukocytes to macrophages and monocytes along with tissue healing. However, a consistent shift in the balance toward cell glycolysis and away from anabolic pathways persists even during chronic inflammation [9, 10].

Neutrophils and the monocyte/macrophage family are cells involved in infection and inflammation that express high levels of GLUT-1 and GLUT-3 and show increased hexokinase activity. Macrophages, which are regarded as a substantial component of 2-[18F]FDG uptake in tumors, are localized as peri-tumoral inflammatory cells [11]. A high degree of 2-[18F]FDG uptake is seen in neutrophils during the acute phase of inflammation, whereas macrophages and polymorphonuclear leukocytes take up 2-[18F]FDG during the chronic phase. A significant linear correlation between 2-[18F]FDG uptake and inflammatory cells density was confirmed in both acute and chronic inflammation [12]. These observations explain the superior accuracy of 2-[18F]FDG PET over traditional imaging techniques in chronic infection/inflammation.

Two major differences are present in the process of 2-[18F]FDG uptake in tumor cells and inflammatory cells. First, glucose-6-phosphatase levels decrease in tumor cells but remain high in inflammatory cells, leading to washout of 2-[18F]FDG from inflammatory cells. The other is the extremely increased GLUT levels in tumor cells compared to inflammatory cells [13]. However, differentiating a tumor from inflammation has always been a clinical challenge with 2-[18F]FDG PET.

7.3 Tissue Infection

Infection of tissues can progress to an acute or chronic phase due to hematogenous spreading of pathogenic microorganisms or local contamination. Tissue infection usually presents with nonspecific signs and symptoms, such that reaching an accurate diagnosis is difficult. Microorganism isolation with multiple sampling or histology of biopsies and imaging provides suggestive information that may hasten the process of diagnosis. When a 2-[18F]FDG PET scan is conducted for the evaluation of malignancy, tissue infection may show positive 2-[18F]FDG uptake that is generally regarded as a false-positive finding. Obviously, 2-[18F]FDG PET has a limitation for differentiating infection from malignant lesions. In general, the mediastinum, hilar, and cervical areas are among those frequently showing nonspecific 2-[18F]FDG uptake, which can lead to inaccurate staging of malignancy.

Although nuclear medicine imaging has not been the first choice for diagnosis and has some limitations, increasing evidence has shown a role for 2-[18F]FDG PET in infectious diseases. 2-[18F]FDG PET is clinically useful for the detection of occult foci of infection in patients with sepsis of unknown origin and with fever of unknown origin (FUO). This is because underlying infectious and inflammatory disorders, such as osteomyelitis, infected vascular grafts, metastatic infectious disease, vasculitis, sarcoidosis, and inflammatory bowel disease (IBD), can be identified with 2-[18F]FDG PET/CT, which is superior to conventional clinical imaging modalities [14].

Recent reports have shown the utility of 2-[18F]FDG PET/CT for diagnosing, treating, and evaluating inflammatory diseases, strongly suggesting that 2-[18F]FDG would be useful in the diagnosis of FUO. 2-[18F]FDG PET may allow easier detection of lesion sites at an early stage, confirmation of pathological diagnosis with precise biopsy or operation, and identification of the etiological agent, which could lead to timely treatment of the underlying disease [15, 16]. The value of 2-[18F]FDG PET for the diagnosis of FUO is described in more detail in Chap. 8.

Diagnosis of postoperative tissue infection is difficult due to various clinical manifestations. Although 2-[18F]FDG may have the potential to indicate the postoperative focal infection site, persistent 2-[18F]FDG uptake in uninfected surgical incisions has been observed after at least several weeks, suggesting that evaluation of a residual tumor by 2-[18F]FDG PET after surgery is unreliable (Figs. 7.1, 7.2, and 7.3).

Fig. 7.1
figure 1

Renal infection in polycystic kidney disease. Focal 2-[18F]FDG uptake is confirmed in the infectious site in the polycystic kidney

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Fig. 7.2
figure 2

Soft tissue infection (cellulitis) at left chest wall

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Fig. 7.3
figure 3

Surgical site infection (duodenum)

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7.4 Osteomyelitis

Osteomyelitis is defined as an infection of the bone, can involve any bone, and is caused by Staphylococcus aureus. Inflammatory markers, plain radiograph, and blood culture are commonly used for the diagnosis of osteomyelitis, although they are not specific for this condition. The presence of inflammatory cells in osteomyelitis results in increased 2-[18F]FDG uptake [17, 18] and contrasts well with low 2-[18F]FDG uptake in normal cortical bone. For acute limb osteomyelitis, clinical evaluation, serum markers of inflammation, and conventional imaging (plain radiographs, magnetic resonance imaging (MRI), or three-phase [99mTc]Tc-hydroxymethylene diphosphonate scintigraphy) have been sufficient to reach a diagnosis. However, 2-[18F]FDG PET has much higher sensitivity and specificity (more than 90%) for the diagnosis of chronic limb osteomyelitis compared to traditional radionuclide and morphological imaging [19,20,21]. Nonetheless, increased osseous 2-[18F]FDG activity has also been observed in inflammatory arthritis, in acute fractures, with significant metal artifacts, and when assessing the postoperative status (persisting 4–6 weeks after the procedure) [22] (Fig. 7.4).

Fig. 7.4
figure 4

Osteomyelitis. Focal 2-[18F]FDG uptake in the right femur, bilateral tibia, and right talus demonstrates osteomyelitis

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Spinal osteomyelitis and discitis are usually caused by direct extension into the spine from adjacent foci or by hematogenous spread. MRI is considered the imaging technique of choice in spinal osteomyelitis with an accuracy of 90%, especially for delineating the extent of soft-tissue, epidural, and spinal cord involvement [23]. 2-[18F]FDG PET is useful in these patients as marrow uptake of 2-[18F]FDG is low, leading to a high target-to-background contrast ratio. 2-[18F]FDG PET shows a higher sensitivity (96%) and specificity (91%) for diagnosing and excluding chronic osteomyelitis compared to combined bone and leukocyte scintigraphy (78% and 84%, respectively) and MRI (84% and 60%, respectively) [24] (Figs. 7.5 and 7.6).

Fig. 7.5
figure 5

Discitis. 2-[18F]FDG uptake is evident at the site of discitis. 2-[18F]FDG PET/CT and MRI images reveal that the inflammation is spread to the upper and lower vertebra

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Fig. 7.6
figure 6

Pyogenic spondylitis. 2-[18F]FDG uptake in the lumber pyogenic spondylitis

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Spinal infection often involves the intervertebral disk, vertebral body, or both due to hematogenic spread or a postsurgical origin. The high spatial resolution of 2-[18F]FDG PET/CT can usually discern bone and soft tissue involvement [25] and is thus used for the diagnosis of osteomyelitis [26]. In a meta-analysis, 2-[18F]FDG PET/CT showed a sensitivity of 97% and specificity of 88% for the diagnosis of spondylodiscitis [27].

For the evaluation of the therapeutic response in patients with osteomyelitis, 2-[18F]FDG PET/CT has a huge potential for making clinical decisions regarding initiation or prolongation of antibiotic therapy or recourse to surgical intervention in 52% of patients with infection [28]. Inflammatory changes in MRI scans can be seen long after the disappearance of the infection, and therefore, 2-[18F]FDG PET appears to be superior to MRI [29].

7.5 Cardiac Device Infection and Inflammatory Diseases of the Heart

2-[18F]FDG PET has a huge potential for the diagnosis of cardiovascular implantable electronic device (CIED) infection. 2-[18F]FDG PET/CT demonstrated a sensitivity of 96% and specificity of 97% for the diagnosis of pocket infections [30] compared to a lower pooled sensitivity of 76% and specificity of 83% for lead infections [31] (Fig. 7.7).

Fig. 7.7
figure 7

Cardiovascular implantable electronic device (CIED) infection. Upper row, pocket infections; lower row, lead infection

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2-[18F]FDG PET/CT has a sensitivity of 73–100%, specificity of 71–100%, positive predictive value of 67–100%, and negative predictive value of 50–100% for prosthetic valve endocarditis [32]. The application of 2-[18F]FDG PET/CT and the Duke criteria increases the sensitivity from 52–70% to 91–97% without compromising specificity [33, 34]. Infective endocarditis is an infection of the endocardial surface of the heart, mainly due to Staphylococcus spp. Transthoracic echocardiography and transesophageal echocardiography have been used for detecting endocardial vegetations with a sensitivity of 40–63% and specificity of 90–100%. Unlike prosthetic valve endocarditis, the role of 2-[18F]FDG PET/CT for the diagnosis of native valve infective endocarditis is limited, with a sensitivity of 14% [35]. In a meta-analysis, 2-[18F]FDG PET/CT showed a sensitivity of 61% for the diagnosis of infective endocarditis [36], which is lower than with the modified Duke criteria (80%) advocated in the European Society of Cardiology (ESC) guidelines [37]. 2-[18F]FDG PET/CT is a valid diagnostic procedure for visualization of infective cardiac valve vegetation and can contribute to the identification of the primary extracardiac infection source or infective emboli in patients with native valve endocarditis, which leads to appropriate intervention and a reduction in the incidence of relapsed infective endocarditis [38].

Pericarditis is caused by viruses in most cases. Other etiologies include tuberculosis (TB), autoimmune diseases, and malignancy [39]. 2-[18F]FDG PET/CT can indicate the existence of active pericarditis. 2-[18F]FDG uptake in TB as an acute infectious disease is higher than in idiopathic pericarditis [40] (Fig. 7.8). Myocarditis is an inflammatory disease of the heart muscle and an important cause of acute heart failure, sudden death, and cardiomyopathy. Echocardiogram is the first-line investigation, and cardiac MRI can provide functional and structural information, useful for further investigation of myocarditis. The role of 2-[18F]FDG PET/CT is not specified and is thus not recommended as a diagnostic strategy for myocarditis.

Fig. 7.8
figure 8

Pericarditis. Diffuse 2-[18F]FDG uptake in the epicardium indicates pericarditis

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A 2-[18F]FDG PET study should be performed after a dietary preparation with a meal of high fat and low carbohydrates to suppress the physiologic cardiac 2-[18F]FDG uptake. Moreover, 2-[18F]FDG PET should generally be performed at least 3 months after the surgical placement of a device [37].

7.6 Vascular Graft Infection (Vascular Prosthesis Infection)

Although vascular prosthesis infection (VPI) is quite a rare occurrence, it is associated with a significant increase in morbidity and mortality risk [41, 42]. Complications regarding early-onset infection include fever, bacteremia, graft dysfunction, thrombosis, and bleeding [43]. Graft infection as a late complication occurs months to years after the procedure and causes graft erosion and pseudoaneurysm. Therefore, long and close observation and early and accurate diagnosis are crucial for the management of patients with suspected VPI (Fig. 7.9).

Fig. 7.9
figure 9

Vascular prosthesis infection (VPI). 2-[18F]FDG uptake seen along the vascular graft indicates VPI; slight 2-[18F]FDG uptake is also seen in the aortic arch aneurysm

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Focal, heterogeneous 2-[18F]FDG uptake around the prosthesis is highly suggestive of VPI. Irregular graft boundaries, soft tissue thickening, or peri-graft fluid collections on concomitant CT also suggest VPI [44]. 2-[18F]FDG PET shows high sensitivity and specificity for the diagnosis (93% sensitivity, 70–91% specificity) of VPI [45]. Several reports showed that image quality assessment using a three-point scale combined with the semiquantitative assessment [46] and a maximum standardized uptake value (SUVmax) cutoff can improve the diagnostic accuracy [47]. Mild to moderate diffuse physiological 2-[18F]FDG uptake has been confirmed in 92% of noninfected vascular prostheses, and this tends to remain in a region of anastomosis [44]. VPI consists of an infected hematoma or a lymphocele around the site of the graft, which leads to decreased specificity of 2-[18F]FDG PET/CT for identifying graft infection. Focal or segmental 2-[18F]FDG uptake is more likely to occur with infection than diffuse uptake [45]. 2-[18F]FDG often accumulates in scar tissue and postoperative site, which can result in false-positive interpretation [48].

7.7 Joint Prosthesis Infection

More than a quarter of patients who have undergone a primary hip or knee arthroplasty will eventually develop symptoms of mechanical loosening after a decade of use. Although prosthetic infection is an uncommon complication that occurs in less than 1% of patients after primary hip or knee arthroplasty, distinguishing between prosthetic infection and mechanical loosening is crucial since the prosthetic infection is a major complication for the patient in terms of prognosis and multistep revision surgery. 2-[18F]FDG PET shows significant heterogeneity in the cumulative test performance for infected prostheses, with sensitivity that ranges from 28% to 91% and specificity that ranges from 9% to 97% [36, 49]. The typical 2-[18F]FDG uptake pattern of prosthetic infection for hip implants is the presence of 2-[18F]FDG uptake between the bone and the prosthesis in the mid-shaft portion of the prosthesis; an accuracy of over 90% has been reported with this pattern [50] (Fig. 7.10). On the other hand, nonspecific 2-[18F]FDG uptake around the head and neck of prostheses frequently occurs and can remain for many years [51]. The site of 2-[18F]FDG uptake is essential for establishing an accurate diagnosis and minimizing false-positive results in patients suspected of having prosthetic infection. However, semiquantitative assessment of 2-[18F]FDG uptake in prostheses is not reliable for differentiating septic and aseptic loosening.

Fig. 7.10
figure 10

Suspected left hip prosthesis infection. 2-[18F]FDG PET/CT shows 2-[18F]FDG uptake around the neck but negative findings at bone-prosthesis interface. The uptake pattern suggests nonspecific 2-[18F]FDG uptake around the head and neck of prostheses

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The test of choice for diagnosing infected prostheses has remained combined labeled leukocyte/marrow imaging over three decades, with an estimated sensitivity of 92–100%, specificity of 91–100%, and accuracy of 91–95% [52,53,54]. 2-[18F]FDG PET shows almost identical sensitivity as labeled leukocyte/marrow imaging, but the specificity is thought to be insufficient using this modality. Thus, at present, although 2-[18F]FDG PET is a worthwhile preoperative modality, the development of better diagnostic criteria is still required.

7.8 Tuberculosis (TB)

TB can involve any organ by hematogenous and/or lymphatic spread. The most commonly involved site of active TB lesions is the lung parenchyma [55, 56], particularly tuberculoma, which typically manifests as a rather discrete nodule or mass with central caseous necrosis surrounded by a mantle of epithelial cells and collagen with peripheral inflammatory cell infiltration [57]. Due to the large number of activated inflammatory cells with high glycolytic rates, active TB lesions are usually represented as areas of intense 2-[18F]FDG uptake. Therefore, the sensitivity of 2-[18F]FDG PET is very high for identifying active granulomatous foci (Fig. 7.11).

Fig. 7.11
figure 11

Tuberculosis. 2-[18F]FDG PET/CT shows tuberculous abscess around the vertebral body and liver

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TB lesions do not have any characteristic 2-[18F]FDG PET features but show variable 2-[18F]FDG uptake according to the grade of inflammatory activity [55]. Due to the lack of specificity of 2-[18F]FDG PET for distinguishing granulomatous disease from malignancy, TB should be considered in the differential diagnosis of 2-[18F]FDG-avid thoracic lesions, and biopsy and histopathological examination are still essential for the final diagnosis.

Nontuberculous mycobacterial (NTM) infection is caused by a group of opportunistic bacterial pathogens such as Mycobacterium avium intracellular complex that is hard to isolate and is characterized by nonspecific clinical signs. In the same manner as TB, NTM might represent a broad range of radiological patterns, comprising parenchymal consolidation, nodular or pseudo-nodular lesions, cavitary lesions, pleural effusions, pleural thickenings, or a mixed pattern [58,59,60]. 2-[18F]FDG PET/CT could reflect the activity and extent of disease by monitoring metabolic activity not only in nodular lesions but also in a broad range of radiologically visible lung lesions in NTM. Despite these uncertainties, an important aspect of PET/CT imaging is its potential role in assessing the extent of disease, its evolution, and follow-up of NTM patients [61].

7.9 Sarcoidosis

Sarcoidosis is regarded as a systemic noncaseating granulomatous disease of unknown etiology. Typical clinical features are bilateral active lymph nodes in the mediastinal and hilar regions. Sarcoidosis also appears as pulmonary lymphoreticular opacities and lesions in the skin, muscle, joints, eyes, and other organs including the myocardium, liver, and spleen [62].

Serum angiotensin converting enzyme is produced by epithelial cells derived from activated macrophages and is a known marker for sarcoidosis that reflects the amount of whole-body granuloma. However, the use of angiotensin converting enzyme (ACE) in sarcoidosis is limited due to its poor sensitivity and specificity [63].

Malignant lymphoma and TB are major differential diagnoses of sarcoidosis; therefore, typical clinicoradiological findings with the histopathological hallmark of noncaseating granulomas are required for the diagnosis of sarcoidosis. 2-[18F]FDG PET/CT is a less-invasive test that can be used to determine targets for tissue sampling and evaluation of the extent of the disease (Fig. 7.12). Compared to gallium-67 scanning, 2-[18F]FDG PET is more sensitive and accurate for detecting pulmonary sarcoidosis, is better for identification of extrapulmonary sarcoidosis, and has higher interobserver agreement [64, 65]. 2-[18F]FDG uptake is correlated with disease activity and the clinical course [66]. 2-[18F]FDG PET is useful for monitoring the treatment response in the early phase, which can be an indication of the success of the management of patients with sarcoidosis [67].

Fig. 7.12
figure 12

Sarcoidosis. Muscular invasion of sarcoidosis

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Myocardial involvement of sarcoidosis is reported in approximately 5% of patients and may lead to a life-threatening condition. Although an endomyocardial biopsy has been conducted for the definitive diagnosis, a sampling error may end in a false-negative result. Therefore, a sensitive imaging technique is required for the diagnosis and monitoring of cardiac sarcoidosis. Delayed gadolinium enhancement in cardiac MRI is a hallmark finding of existing lesions and a poor prognostic factor [68, 69]. 2-[18F]FDG PET and cardiac MRI in patients with suspected cardiac sarcoidosis show a sensitivity comparable to 2-[18F]FDG PET (87.5% versus 75%, respectively) but with lower specificity (38.5% versus 76.9%, respectively) [70]. 2-[18F]FDG PET/CT can be implemented in cardiac sarcoidosis patients with a cardiac device unable to undergo MRI.

Focal heterogeneous 2-[18F]FDG uptake in the myocardium indicates active myocardial sarcoidosis (Fig. 7.13). However, myocardial physiological 2-[18F]FDG uptake shows a variable pattern; therefore, special preparation to suppress glucose consumption in the myocardium is required to reduce background physiological myocardial 2-[18F]FDG uptake. During fasting states in aerobic conditions, the human myocardium preferentially utilizes energy derived from free fatty acids. Therefore, focal patchy myocardial uptake reflecting active myocardial sarcoidosis will emerge [71]. A prolonged interval of fasting for more than 12 h (recommended 18 h or more) leads to a decrease in blood glucose and insulin levels and an increase in blood free fatty acid levels, minimizing physiological 2-[18F]FDG uptake in the normal myocardium [8]. As dietary modification prior to 2-[18F]FDG PET, a low-carbohydrate diet of less than 5 g the night before 2-[18F]FDG PET is recommended to reduce blood glucose and insulin levels [72, 73]. An Atkins-style low-carbohydrate diet (less than 3 g) on the day before PET together with overnight fasting effectively suppresses myocardial 2-[18F]FDG uptake compared to overnight fasting alone [74]. False-positive nonhomogeneous 2-[18F]FDG uptake in the myocardium due to poor patient preparation results in a characteristic pattern of 2-[18F]FDG uptake in the basal and lateral walls [75].

Fig. 7.13
figure 13

Sarcoidosis. 2-[18F]FDG PET/CT demonstrates mediastinal and abdominal lymphadenopathies accompanied by cardiac sarcoidosis

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7.10 Autoimmune Diseases

7.10.1 Vasculitis

Systemic vasculitis is characterized by inflammation with infiltration of leukocytes into the blood vessels and reactive damage to mural structures. Classification of vasculitis was first advocated in the Chapel Hill Consensus Conference (CHCC1994) with consensus on names for the most common forms of vasculitides and to construct a specific definition for each type [76]. Due to the emergence of new knowledge about vasculitis, the International Chapel Hill Consensus Conference (CHCC2012) was advocated to improve the CHCC1994. In CHCC2012, names and definitions of vasculitides were changed, and important categories of vasculitides were newly added [77].

Vasculitis is difficult to diagnose due to the absence of specific symptoms. For the diagnosis of large vessel vasculitis (LVV), CT is useful for detecting wall thickening, calcification, and mural thrombi. CT angiography demonstrates luminal changes (stenosis, occlusion, dilatation, and aneurysm). MRI can provide detailed information about structural vascular abnormalities (aneurysms, stenosis) but does not identify inflammation in structurally normal blood vessels.

Because of the limited spatial resolution of the PET/CT scanner, 2-[18F]FDG PET/CT can only visualize LVV, which is defined as a disease mainly affecting the large arteries, with two major variants, Takayasu arteritis (TA) and giant cell arteritis (GCA) (Fig. 7.14). However, the advantage of 2-[18F]FDG PET/CT is that it can detect areas affected by vasculitis in the early phase prior to structural changes. TA and GCA are different diseases with different ages of onset, ethnic distributions, immunogenic backgrounds [78], and response to therapies [79, 80]. TA mainly affects the aorta and its main branches, namely, the carotid arteries, brachiocephalic trunk, and subclavian arteries. GCA can involve the temporal artery as well as the aorta and its main branches (Fig. 7.15). However, GCA and TA also show some overlap regarding the histopathology of arterial lesions, reflecting shared pathways in tissue inflammation [79, 81].

Fig. 7.14
figure 14

Vasculitis (Takayasu arteritis). Smooth liner 2-[18F]FDG uptake in the aortic arch and abdominal aorta, which is a typical 2-[18F]FDG uptake pattern in large vessel arteritis

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Fig. 7.15
figure 15

Vasculitis (giant cell arteritis). 2-[18F]FDG uptake in the temporal arteries and cervical arteries. 2-[18F]FDG uptake in the temporal arteries is frequently seen in giant cell arthritis

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The sensitivity and specificity of 2-[18F]FDG PET for the diagnosis of TA are 92% and 100%, respectively. The sensitivity and specificity of 2-[18F]FDG PET for the diagnosis of GCA are 77–92% and 89–100%, respectively [80, 82].

GCA is associated with polymyalgia rheumatica (PMR), an inflammatory disease around the joints that causes pain and stiffness. Typical 2-[18F]FDG image patterns of PMR include uptake in glenohumeral synovia, subacromial-subdeltoid bursa, supraspinatus tendinitis, and biceps synovitis (shoulder); trochanteric/ischial bursa; hip synovia; interspinous regions of the cervical and lumbar vertebrae; or the synovial tissue of the knees [83] (Fig. 7.16). Nearly half of the patients with GCA can present with PMR as a complication, whereas approximately 20% of patients with PMR might develop GCA [84, 85].

Fig. 7.16
figure 16

Polymyalgia rheumatica (PMR). PMR often coexists with giant cell arteritis

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Interpretation criteria proposed to assess the vasculitides have a visual 0 to 3 grading scale (0 = no uptake (≤mediastinum); 1 = low-grade uptake (<liver); 2 = intermediate-grade uptake (= liver), 3 = high-grade uptake (>liver)), with grade 2 possibly indicative of and grade 3 considered positive for active LVV [86]. A total vascular score that includes the visual grading scale is another reasonable method that can be used to evaluate not only the activity of vasculitis but also the extent of the disease by summing up the 2-[18F]FDG uptake scores at seven different vascular regions (thoracic aorta, abdominal aorta, subclavian arteries, axillary arteries, carotid arteries, iliac arteries, and femoral arteries) [83, 87]. The target-to-background ratio, using the blood pool as a reference, is a possible semiquantitative method for the evaluation of vasculitis [88, 89], whereas SUV itself is not recommended due to the large overlap between patients with vasculitis and normal cases and the low specificity [88, 90].

Although 2-[18F]FDG PET has the potential for monitoring the response to therapy, no definitive result has led to such recommendation. Several reports showed a difference in 2-[18F]FDG uptake between baseline and post-corticosteroid therapy. 2-[18F]FDG uptake is reduced several months after the initiation of therapy, but it has no evidence of utility in further 2-[18F]FDG scans or for prediction of disease relapse [91, 92].

Atherosclerotic vascular uptake is observed with aging and can result in false-positive findings in the evaluation of LVV. Typical 2-[18F]FDG PET finding is uptake in iliofemoral arteries, a feature of atherosclerosis. This should be taken into consideration in the assessment of LVV [93, 94].

Polyarteritis nodosa is a systemic necrotizing vasculitis, which occurs in the medium- and small-sized arteries and causes multiple aneurysms. A recent report shows the utility of 2-[18F]FDG PET/CT for the early diagnosis of polyarteritis nodosa [95].

Vasculitis is often accompanied by other autoimmune diseases, and therefore, careful observation of whole-body PET imaging should be done to monitor other disease etiologies [96,97,98,99].

7.10.2 Inflammatory Bowel Diseases (IBD)

IBD is a chronic immune-mediated inflammatory disease that occurs in the gastrointestinal tract. Crohn’s disease and ulcerative colitis are the representative diseases of IBD. 2-[18F]FDG PET/CT is a highly sensitive method to detect areas of active IBD. A meta-analysis revealed overall pooled sensitivity and specificity of 85% and 87% for 2-[18F]FDG PET, respectively [100] (Fig. 7.17). Another indication for 2-[18F]FDG PET may be for children, adolescents, and high-risk patients with IBD who appear to have difficulty undergoing an invasive endoscopy. Visual analysis of PET images is most accurate for diagnosis, whereas SUVs of 2-[18F]FDG are not correlated with any indicators of Crohn’s disease activity (C-reactive protein or inflamed segments confirmed with endoscopy) [101].

Fig. 7.17
figure 17

Inflammatory bowel disease (IBD). Upper row, Crohn’s disease (small intestine); lower row, ulcerative colitis (sigmoid colon)

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However, variable physiological 2-[18F]FDG uptake in the bowel, such as uptake at the ileocecal junction, uptake in areas of small bowel peristalsis, and diffuse uptake in the ascending colon [102], might be observed. Therefore, detection of IBD with 2-[18F]FDG PET/CT still has major limitations. The specificity of 2-[18F]FDG PET can be increased by combining 2-[18F]FDG uptake with the anatomical accuracy of CT [100, 103]. The presence of certain features, such as bowel wall thickening, loop separation, mesenteric injection, and fat stranding, on concomitant CT, helps discern physiological from pathological uptake. The addition of intravenous iodinated contrast enhancement can provide more precise information about mural enhancement or increased thickness of the bowel wall [104]. 2-[18F]FDG PET/CT shows the potential for treatment monitoring of IBD with steroids or infliximab [105].

7.10.3 IgG4-Related Disease

The IgG4-related disease is characterized by the formation of mass-forming lesions in various organs that consist of lymphoplasmacytic infiltrates and fibrosclerosis [106, 107]. This disease was traditionally thought to consist of disparate clinical entities, such as autoimmune pancreatitis, Mikulicz disease, and primary sclerosing cholangitis. The IgG4-related disease is highly sensitive to corticosteroids. However, it mimics malignancy that may require surgery or chemoradiotherapy, and therefore, accurate diagnosis is crucial for the management of patients. Increased serum immunoglobulin (Ig)G4 was initially thought to be the major diagnostic criterion for IgG4-related disease. Now, clinicians know that elevated IgG4 is not present in all patients with histologically proven IgG4-related disease and that the IgG4 is not specific for this disease. 2-[18F]FDG PET/CT can identify the disease distribution and activity in IgG4-related disease and is also useful for determining biopsy sites for pathological diagnosis. PET/CT indicates a larger extent of organ involvement than assumed before imaging in 70% of patients with IgG4-related disease [108] (Fig. 7.18).

Fig. 7.18
figure 18

IgG4-related disease (interstitial nephritis). 2-[18F]FDG uptake in bilateral kidneys without a clear border between the cortex and medulla of the kidneys

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Autoimmune pancreatitis (AIP) is one of the major IgG4-related diseases and should be distinguished from pancreatic cancer. Compared to pancreatic cancer, AIP tends to show extra-pancreatic lesions and multiple foci of 2-[18F]FDG uptake in the pancreas [51]. Mikulicz disease and primary sclerosing cholangitis are also major IgG4-related diseases. The other reported sites of IgG4-related involvement include the meninges, lacrimal gland, salivary gland, thyroid gland, lung, breast, liver, kidney, prostate, and skin [107].

IgG4-related vasculitis is thought to be categorized as a primary type of vasculitis and a secondary form of vascular involvement characterized by periaortic or periarterial involvement [109]. Macrovascular manifestations of IgG4-related disease have been reported as inflammatory aortic aneurysm [110], coronary periarteritis [111], and periaortitis/arteritis in the setting of retroperitoneal fibrosis [112, 113]. IgG4-related vasculitis can lead to morbidity and mortality in the form of aortic dissection and sudden cardiac death [114]. 2-[18F]FDG uptake is confirmed in the area of IgG4-related soft tissue thickening with active inflammation around arteries such as coronary arteries [115,116,117].

The differential diagnosis of IgG4-related disease is malignant lymphoma, which requires different treatment than IgG4-related disease. IgG4-related lymphadenopathy with atypical lymphoplasmacytic and immunoblastic proliferation shows histological characteristics that are often confused with malignant lymphoma, especially angioimmunoblastic T-cell lymphoma, which typically presents with polyclonal hypergammaglobulinemia [107, 118]. IgG4-related mucosa-associated lymphoid tissue lymphoma and IgG4-producing lymphoma in ocular adnexal regions have also been reported [119].

Glucocorticoids have been considered first-line therapy for active, untreated IgG4-related disease [120]. PET/CT is a promising tool not only for the diagnosis of IgG4-related disease but also for monitoring of disease activity. However, hyperglycemia due to diabetes mellitus induced by steroid therapy may influence 2-[18F]FDG uptake, and steroid therapy itself could lead to overestimation of the response (Fig. 7.19).

Fig. 7.19
figure 19

IgG4-related vasculitis. 2-[18F]FDG uptake is seen in the outer part of large vessels

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7.10.4 Rheumatoid Arthritis (RA)

RA is an autoimmune chronic inflammatory disorder that mainly affects the joints with synovitis, pannus formation, and cartilage erosion and sometimes affects the skin, eyes, lungs, heart, and blood vessels. 2-[18F]FDG uptake has been confirmed at the sites affected by RA with higher sensitivity early after the onset of clinical symptoms (Fig. 7.20). The degree of 2-[18F]FDG uptake in affected joints reflects disease activity, which correlates with serum blood markers of inflammation (erythrocyte sedimentation rate [ESR], C-reactive protein), disease activity score, symptoms such as swelling and tenderness of joints, ultrasonography findings of synovitis and synovial thickening, and power Doppler studies for neovascularization [121,122,123].

Fig. 7.20
figure 20

Rheumatoid arthritis. Symmetrical 2-[18F]FDG uptake in large joints is a typical feature of rheumatoid arthritis. 2-[18F]FDG uptake at atlantoaxial joint may suggest the future occurrence of atlantoaxial subluxation which is an important and potentially life-threatening complication of rheumatoid arthritis

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Although little evidence exists for the utility of 2-[18F]FDG PET/CT for the evaluation of therapeutic response, several reports show promising results in predicting the outcome of traditional treatment [124] and treatment with biologicals such as anti-tumor necrosis factor-α [123, 125, 126]. Moreover, 2-[18F]FDG PET/CT can predict the outcome earlier than other types of morphological imaging [123, 126]. Due to insufficient evidence and according to the European League Against Rheumatism (EULAR) recommendation, 2-[18F]FDG PET is not recommended as an imaging tool for the diagnosis or therapy evaluation in RA [127].

7.10.5 Other Autoimmune Diseases

Limbic encephalitis is mainly caused by a viral infection (typically herpes simplex virus) and an autoimmune response against the limbic system. Autoimmune limbic encephalitis has two types: the paraneoplastic and non-paraneoplastic. The specific feature seen on 2-[18F]FDG PET imaging is hypermetabolism in the temporal and orbitofrontal cortices and hypometabolism in the occipital lobe and bilateral basal ganglia [128, 129].

Multiple sclerosis is thought to be an autoimmune disease that leads to demyelination in the central nervous system. 2-[18F]FDG PET shows hypometabolism at demyelinated sites in the white matter, in addition to changes in glucose metabolism in the cortex [130].

7.11 Immune Deficiency (HIV-Related Disease)

Approximately 36.9 million people worldwide were living with HIV/AIDS in 2017. An estimated 1.8 million individuals worldwide became newly infected with HIV in 2017 [131]. AIDS-related morbidity and mortality have decreased due to advanced treatment options, advances in treatment access, and the establishment of effective prevention strategies, in addition to the low rate of new infections even in high-burden countries. The clinical manifestations of patients with HIV are variable and include a wide range of infections, malignancies, neurological disorders, and lifestyle diseases [132].

2-[18F]FDG uptake in lymph nodes of HIV patients is positively correlated with viral replication and inversely correlated with CD4 counts [133, 134]. This specific 2-[18F]FDG uptake is often misleading in the assessment of HIV-associated malignancies in patients with HIV infection (Fig. 7.21). 2-[18F]FDG PET is useful for distinguishing primary central nervous system lymphoma from opportunistic infections such as toxoplasmosis [135, 136].

Fig. 7.21
figure 21

HIV infection. The image on the left side shows nonspecific lymphadenopathies frequently seen in a patient with HIV infection. The image on the right side shows angioimmunoblastic T-cell lymphoma in a patient with HIV infection

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In immunosuppressed patients, pulmonary TB occurs in an atypical pattern and increases the risk of extrapulmonary lesions. 2-[18F]FDG PET can be used to evaluate the distribution of TB lesions in the whole body [137, 138]. 2-[18F]FDG PET/CT has proven useful for ascertaining the source of infection in HIV-related FUO [139].

7.12 Conclusion

This chapter introduces the impact of 2-[18F]FDG PET for the diagnosis and assessment of treatment in infections, inflammatory, and autoimmune diseases. 2-[18F]FDG PET can provide higher resolution images than conventional nuclear medicine examinations. Moreover, 2-[18F]FDG PET has the advantage of completing a whole-body scan in a short time. However, the utility of 2-[18F]FDG PET varies greatly, and the underlying mechanism of each disease still remains to be elucidated. Compared to malignancy, evidence for the usefulness of 2-[18F]FDG PET is still weak for assessing infections, inflammatory, and autoimmune diseases. Therefore, further evaluation will be required to determine the role of 2-[18F]FDG PET in these contexts.