Infection a nd Infl a mm a tion 2 4

24

Infection and Inflammation

Marc P. Hickeson

Positron emission tomography (PET) with fluorine-18 (

F)-fluoro-2- deoxyglucose (FDG) has been proven to be a valuable noninvasive imaging modality for the diagnosis, staging, and monitoring of therapy for various malignancies. In addition, studies are demonstrating the value of FDG-PET for the evaluation of nononcologic conditions. Based on the literature, conditions such as osteomyelitis, fever of unknown origin (FUO), acquired immunodeficiency syndrome (AIDS), vasculi- tis, and inflammatory bowel disease can be successfully imaged with FDG-PET. With the approval of additional PET radiotracers in the future, there will be more widespread applications of PET for inflam- matory and infectious disorders.

Unlike anatomic imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound, PET is a mol- ecular imaging modality that detects metabolic abnormalities present in the disease before structural abnormalities become evident. In addi- tion to FDG, other radiopharmaceuticals are available for scintigra- phic imaging such as technetium-99m (

Tc)-hexamethylpropylene- amine-oxime (HMPAO)-labeled leukocytes, indium-111 (

In)-oxime labeled leukocytes, gallium-67 (

Ga) citrate,

Tc-labeled antigranulo- cyte monoclonal antibodies, and

Tc-labeled immunoglobulins.

Advantages of FDG-PET as compared with the aforementioned radio- pharmaceuticals for the imaging of inflammation and infection include the ability to provide a result as early as 1

/

to 2 hours after tracer injec- tion, the relatively low radiation dose, and the excellent spatial resolu- tion and lesion-to-background contrast. These advantages contribute to the superior accuracy of FDG-PET for the diagnosis or exclusion of infections.

Clinical Applications of FDG-PET

The specific clinical applications of FDG-PET are as follows:

1. Osteomyelitis

2. Fever of unknown origin (FUO) (discussed in Chapter 23)

448

3. Acquired immunodeficiency syndrome (AIDS) 4. Vasculitis

5. Inflammatory bowel disease (IBD) 6. Thyroiditis

7. Chronic granulomatous disease (CGD)

Osteomyelitis

Although there is limited literature about FDG-PET imaging of osteomyelitis specifically in the pediatric population, FDG-PET has been shown to have a promising role for imaging bone infection in the general population (1–5). This is due to the high metabolic state and increase glucose accumulation by the inflammatory cells (6).

Unlike in adults, osteomyelitis in children usually results from hematogenous spread of microorganisms to bones. Infection usually affects a single bone and typically involves the metaphysis of long bone, most commonly the tibia, femur, or humerus. The clinical pre- sentation of osteomyelitis includes local pain and swelling, fever, chills, and malaise. The most common infecting organisms are streptococci and Staphylococcus aureus in neonates, and S. aureus in the pediatric population. The diagnosis can usually be established with positive triple-phase bone scintigraphy and blood culture.

Although bone scintigraphy is highly sensitive and specific for the diagnosis of osteomyelitis in intact bone, interpretation is complicated in the presence of a coexisting fracture and surgical intervention at the site of suspected osteomyelitis. In this latter setting, further imaging using an infection radiotracer such as

Ga,

In-labeled leukocytes, and

18

F-FDG is often necessary to increase the specificity for osteomyelitis.

The most specific method is with

In-labeled leukocytes; however, this is sensitive only for acute infection.

Ga is preferred to

In-labeled leukocytes for the detection of chronic infection (7,8). Fluorodeoxy- glucose-PET also shows promise for the evaluation of chronic osteomyelitis. Unlike other nuclear medicine imaging modalities, FDG- PET provides good spatial resolution and intrinsic tomographic images, which allow differentiation of soft tissue infection from osteomyelitis. It also provides results within 3 hours after FDG injec- tion, which is shorter than the few days required with

Ga imaging.

It is also known that hypermetabolism seen on FDG-PET at the site of fractures normalizes relatively rapidly. A fracture may be associ- ated with increased FDG uptake for up to 3 months (9). For this reason, FDG-PET facilitates differentiation of a noncomplicated frac- ture of greater than 3 months from a pathologic fracture (i.e., infection), and thus is not useful before 3 months. A negative FDG-PET study essentially rules out osteomyelitis (5). Fluorodeoxyglucose-PET also has promise for the monitoring the response to antimicrobial therapy (3).

In summary, FDG-PET is a functional imaging modality with high

sensitivity for diagnosis of acute and chronic osteomyelitis. The value

of PET is limited for the evaluation of acute uncomplicated

osteomyelitis. However, in the minority of the cases of osteomyelitis

involving nonintact bone, FDG-PET has great promise for diagnosis and for monitoring the response to antimicrobial therapy.

Acquired Immunodeficiency Syndrome

Acquired immunodeficiency syndrome (AIDS) is an infectious disease caused by human immunodeficiency virus (HIV). Morbidity and mor- tality from HIV infection most commonly occur not from the HIV infec- tion itself but from the malignancies and opportunistic pathogens associated with AIDS.

O’Doherty et al. (10) studied the role of PET scanning in patients infected with HIV. Fluorodeoxyglucose-PET scan had a sensitivity and specificity of 92% and 94%, respectively, for the localization of focal pathology requiring treatment. The positive predictive value was greater than for hypermetabolic foci on FDG-PET with intensity greater than that of the liver. Fluorodeoxyglucose-PET can help localize a wide variety of infections such as Cryptococcus neoformans, Pneumocystis carinii pneumonia, Pseudomonas aeruginosa, Mycobacterium tuberculosis, and Mycobacterium avium intracellulare (Fig. 24.1). Furthermore, ima- ging with FDG using a dual-head coincidence imaging system was shown to provide a higher sensitivity than with

Ga imaging for the demonstration of a focus of infection in patients with AIDS (11).

Positron emission tomography has played a major role in the man- agement of AIDS with central nervous system (CNS) lesions. Patients with HIV who present with a change in mental status or abnormal neu- rologic signs often have CNS lesions demonstrated on a CT scan or MRI. Toxoplasmosis is the most common infectious etiology of focal CNS lesions, and malignant lymphoma is the most common CNS malignancy in HIV-infected patients. Thallium-201 (

Tl) and

Tc- sestamibi have been used for the differentiation of toxoplasmosis and lymphoma in HIV-infected patients presenting with intracranial mass lesions. Heald et al. (12) reported that FDG-PET has a high accuracy

A B C

D

LE GHT

IGHT LE

FOOT FOOT

Figure 24.1. Fluorodeoxyglucose (FDG)-PET attenuation corrected imaging demonstrates diffuse and

bilateral increased FDG uptake in the lungs. Maximal intensity projection (A), transaxial (B), sagittal

(C), and coronal (D) are shown. The final diagnosis was Pneumocystis carinii pneumonia established by

bronchoalveolar lavage.

for the differentiation of CNS lymphoma from infections in the setting of brain mass lesions (Fig. 24.2). Lymphoma is associated with intense hypermetabolism as compared to infections. In that study, there were two false-positive cases due to progressive multifocal leukoen- cephalopathy demonstrating intense hypermetabolism on FDG-PET.

Studies are currently under way to assess the accuracy of FDG-PET for the characterization of brain lesion in patients with AIDS (Fig. 24.2).

Fluorodeoxyglucose-PET has great promise to become a standard modality for localization, for the determination of the extent of oppor- tunistic infections, and for the differentiation of CNS lymphoma from opportunistic infection in patients with brain mass lesions associated with AIDS.

Vasculitis

Vasculitis is defined as an inflammatory process associated with accu- mulation of leukocytes in the blood vessel wall and reactive damage to the mural structures. It is typically classified by the size of vessels most commonly involved by the disease. In several studies, FDG-PET has been shown to be useful for the evaluation of large vessel vasculi- tides, such as Takayasu disease and giant cell arteritis in arteries mea- suring more than 4 mm in diameter (13–21), particularly for the initial diagnosis and for the assessment of response to treatment.

In children, Kawasaki disease (KD) and Henoch-Schönlein purpura are the most common vasculitides. Kawasaki disease is a vascular inflammatory disorder of unknown etiology that is usually self-limited.

A B

C D

Figure 24.2. Biopsy-proven central nervous system (CNS) lymphoma involv-

ing the left parietal lobe shown on FDG-PET maximal intensity projection

images in the anterior (A), right lateral (B), posterior (C) and left lateral (D)

projections.

The clinical manifestations include fevers, erythema, edema, mucosi- tis, lymphadenopathy, and conjunctivitis. Diagnosis is usually estab- lished by history and physical examination. The most serious complication is myocardial infarction, for which echocardiogram is used for the evaluation of KD. Fluorodeoxyglucose-PET has been shown to be helpful for the evaluation for myocardial viability in patients with KD and previous myocardial infarct (22). Henoch- Schönlein purpura is a small vessel inflammatory disease to the skin, kidneys, gastrointestinal tract, lungs, and CNS. Because the small vessels are the predominant sites of involvement, FDG-PET is not expected to be a sensitive modality for the diagnosis of Henoch- Schönlein purpura.

In the adolescence population, Takayasu arteritis (TA) is the most common cause of vasculitis. It is a large vessel granulomatous inflam- matory process affecting the aorta and its major branches. The signs and symptoms are nonspecific, such as fevers, weight loss, and lethargy. Because of the nonspecificity of these symptoms, TA may be undiagnosed for several months to years. Complications include aortic aneurysms, rupture, stenosis and thrombus, congestive heart failure, ischemic strokes, and end-organ infarcts. The diagnosis of TA is estab- lished by invasive angiography or MR angiography. However, diag- nosis is difficult because the structural changes seen by contrast angiography are only seen late during the disease. Magnetic resonance angiography is currently becoming the modality of choice for diagno- sis early in the disease. It would demonstrate the inflammatory wall thickening of the involved vessel in the early phases of the disease.

Positron emission tomography with FDG also has promise in the eval- uation of patients with TA. Hara et al. (23) reported a case of early TA in which the involved vessels demonstrated increased FDG uptake on PET imaging. Meller et al. (24) have shown subsequently in a study of five patients that FDG-PET is a suitable modality for the diagnosis of early TA (Fig. 24.3). In another study that included 15 patients, one with TA, FDG-PET detected more vascular areas involved by the inflam- matory process than did the MRI (25). Fluorodeoxyglucose-PET has also been shown to be a promising modality for the early evaluation of the response to treatment of vasculitis (15,17) as the FDG-PET scan normalizes following successful treatment. Fluorodeoxyglucose-PET shows the potential to have an important role in the early diagnosis and monitoring treatment of patients with large and medium vessel vasculitis (Fig. 24.3).

Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is an inflammatory disease that

affects the gastrointestinal tract. The etiology is uncertain but is prob-

ably immune-mediated. There are two main categories of IBD: Crohn’s

disease and ulcerative colitis. Crohn’s disease can involve any region

along the gastrointestinal tract from the mouth to the anus, and typi-

cally presents with diarrhea, abdominal pain, and weight loss. Ulcera-

tive colitis involves the rectum and extends proximally, is limited to the

large intestine, and typically presents with bloody diarrhea, abdomi- nal pain, and tenesmus. There are several extraintestinal manifestations of IBD, which include ocular manifestations, nephrolithiasis, arthropa- thy most commonly affecting large joints, primary sclerosing cholan- gitis, and erythema nodosum.

Positron emission tomography is a noninvasive modality that was reported to be helpful for the detection of disease activity in patients

A

B

Figure 24.3. Initial FDG-PET images in the coronal and sagittal planes demon-

strating intense FDG activity in the thoracic aorta (large arrows). Follow-up

study demonstrated normalization in the ascending aorta (small arrow) and

partial resolution in the descending aorta (medium arrow). [Source: Meller

et al. (25), with permission of Springer.]

with IBD (26). However, the presence of physiologic FDG activity in the large intestine can affect the sensitivity and specificity of PET for the evaluation of IBD. Despite this limitation of FDG-PET, Neurath et al. (27) reported a sensitivity of 85% with FDG-PET for the demon- stration of disease activity in Crohn’s disease, which was significantly superior to that of other noninvasive imaging methods including MRI and leukocyte scintigraphy, and a specificity of greater than 89%.

Recently, investigators demonstrated clinically feasible methods of labeling FDG with leukocytes (28). The PET images with FDG-labeled leukocytes demonstrate minimal tracer activity in the healthy gas- trointestinal and urinary tract as compared to FDG-PET images. There- fore, PET with FDG-labeled leukocytes provides abdominopelvic images with minimal hindrance from physiologic distribution of the radiotracer. The intensity of foci of FDG-labeled leukocytes activity cor- related well with the degree of inflammation on histology (28).

In brief, FDG-PET is a noninvasive modality that has shown great promise for the detection of inflamed segments in patients with IBD.

Studies are currently under way to assess the accuracy of FDG-labeled leukocytes, which will provide abdominopelvic images that are not hindered by normal physiologic activity in the gastrointestinal and urinary tract.

Thyroiditis

Thyroiditis is defined as an inflammatory process involving the thyroid. Although it is most prevalent between the third and fifth decades of life, it has been reported at all ages. Several types of thy- roiditis exist, most commonly chronic lymphocytic (Hashimoto’s) thy- roiditis, subacute thyroiditis, and silent thyroiditis.

Thyroiditis can present incidentally as diffuse hypermetabolism involving the thyroid gland on FDG-PET (29–31). The differential diag- nosis for diffuse hypermetabolism in the thyroid glands includes Graves’ disease (32) and subclinical hypothyroidism associated with elevated serum thyroid-stimulating hormone (TSH) without any other thyroid pathology (33). Thyroiditis can be distinguished from thyroid cancer, which usually demonstrates focal hypermetabolism in the nodule.

In summary, the presence of diffuse hypermetabolism of the thyroid should raise the suspicion of subclinical hypothyroidism or thyroiditis in patients without symptoms of hyperthyroidism.

Chronic Granulomatous Disease

Chronic granulomatous disease (CGD) is a rare primary immunodefi-

ciency disorder that results in recurrent, often life-threatening, bacter-

ial and fungal infections. The vast majority of patients first presents

during infancy or childhood. Chronic granulomatous disease is sus-

pected to result from the inability of the phagocytes to produce ade-

quate quantities of superoxide radicals to kill catalase positive bacteria

and fungi. The diagnosis is established by determining the phagocytic

cells’ oxidase activity. Treatments for patients with CGD include

aggressive treatment of infection, lifelong antibiotic prophylaxis, and g-interferon therapy. This disease can be cured by bone marrow trans- plantation, provided that the patient does not have any underlying infection at the time of transplant (34).

Computed tomography scan has a valuable role in localizing the sites and extent of infectious foci in CGD patients. However, it cannot differentiate active lesions from chronic inactive lesions.

Fluorodeoxyglucose-PET is a suitable imaging modality that can dif- ferentiate active infectious lesions from chronic inactive lesions by the presence of increased FDG accumulation in inflammatory tissues (6,26). In a study involving seven children with CGD, FDG-PET was compared with CT scan for the accuracy of the detection of infective foci (35). The number of lesions detected by FDG-PET and CT scan was 116 and 126, respectively. Fifty-nine lesions suspicious for active infec- tion on CT scan were excluded by PET, and an additional 49 infectious lesions not seen on CT were detected by PET. The infectious agents were identified in all seven patients based on the FDG-PET results.

Early identification of active lesions and differentiation of active lesions from chronic inactive lesions with therapy are important to prevent drug-related toxicities from ineffective or inappropriately prolonged treatment (Fig. 24.4).

In summary, FDG-PET is useful for the management of patient with CGD. It provides the ability to differentiate active infection from chronic inactive granuloma. A positive PET scan indicates that infection is present and that the abnormal hypermetabolic focus can be biopsied. A negative PET scan indicates that there is no evidence of infection. This would justify the discontinuation of aggressive,

A B

C D

L L

P

L

R

Figure 24.4. Corresponding transaxial images of FDG-PET (A,C) and CT scan

(B,D) showing inactive lesion (A,B) and active lesions (C,D) due to Actinomyces

naeslundii. [Source: Gungor et al. (35), with permission from the BMJ Publish-

ing Group.]

potentially toxic antimicrobial treatment and qualify the patient to be a candidate for bone marrow transplantation.

Differentiation of Infectious or Inflammatory Processes from Malignancy

18

F-fluoro-2-deoxyglucose is a glucose analogue. Its accumulation is not specific to tumors. It has been demonstrated that tumors as well as inflammatory and infectious processes frequently accumulate FDG (5,36), which may result in false-positive interpretation of FDG-PET for the presence of tumors. Tumors typically exhibit more intense FDG activity than inflammatory and infectious lesions. The standard uptake value (SUV) is a semiquantitative measurement of the intensity of uptake (see below). However, there is considerable overlap of the SUV of benign and malignant lesions. This makes the differentiation of benign from malignant lesions difficult if only one time point is used for imaging, particularly for lesions with mild to moderate FDG intensities (SUVs ranging from 1 to 5). The SUV can be calculated as follows:

It has been demonstrated that the intensity of FDG accumulation in inflammatory tissues is maximal at approximately 60 minutes after injection and gradually decreases afterward (37). Lodge et al. (38) sub- sequently reported significantly different time-activity responses of benign and malignant lesions. Benign lesion peak FDG activity occurred within 30 minutes, whereas malignant lesions’ maximal activ- ity occurred at approximately 4 hours after injection. The different FDG uptake patterns may be attributed to the different enzymatic expression of hexokinase and glucose-6-phosphatase in benign and in malignant lesions. Tumors typically exhibit decreased glucose-6- phosphatase activity as compared to benign lesions (39,40). As a result, the hexokinase/glucose-6-phosphatase ratio is increased in tumors, which may explain why tumors demonstrate increasing FDG accumu- lation over a longer period of time after injection. Unlike tumors, mononuclear cells, which predominate in chronic inflammatory processes, have increased glucose-6-phosphatase activity (41). This may account for the shorter time to peak FDG accumulation after injec- tion as compared with tumors. For this reason, dual-time point imaging is sometimes helpful for the differentiation of benign from malignant lesions.

Dual-time point imaging with FDG-PET is a technique that has been found to be helpful for distinguishing tumors from benign lesions in various conditions (42–45). In this technique, the first scan is performed using the same method as in single-time point imaging. The second scan is performed in the site of the lesion in question. Factors affecting the accuracy of this technique are the time of the first scan after injec- tion and the time interval between the first and second scans. Because

SUV Activity in MBq mL Decay factor of F after injection Injected dose in MBq Body weight in g

= ¥ ( )

¥

18 -1

FDG uptake by inflammatory cells peaks in intensity at about 60 minutes after injection, the suggested time of the first scan should be at least 60 minutes after FDG administration. The time interval between the first and second scans should be at least 30 minutes to provide ade- quate additional accumulation of FDG in tumors and differentiation between benign lesions and tumors (Fig. 24.5) (45). The positive inter- pretation criterion of this technique is an increase in SUV by at least 10% between the first to second scans (43).

Dual-time point imaging is a helpful technique for differentiat- ing benign from malignant lesions, particularly for those with mild or moderate FDG accumulation. Malignant lesions increase in intensity on delayed imaging, and benign lesions demonstrate stable or decreas- ing intensity on delayed imaging.

Conclusion

Positron emission tomography is a noninvasive modality that shows great promise for the evaluation of patients with infections. The most commonly used radiopharmaceutical is FDG. With the availability of further studies, infection and inflammation may become a major clin- ical indication for FDG-PET in the clinical practice of medicine.

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