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A
variety of nuclear medicine imaging techniques oxime (HMPAO) leukocytes have been shown to retain
provide effective methods for the detection and their innate function and have demonstrated relatively high
assessment of both clinically apparent and occult sensitivity and specificity for acute infections. However,
infectious and inflammatory conditions. Rather than repre- sensitivity may be somewhat lower for chronic infections.
senting organ-specific techniques, these procedures use The procedure involves removing some of the patient’s
radiopharmaceuticals that localize preferentially in inflamed own leukocytes, labeling them, and reinjecting them before
or infected tissue in any location in the body. The available scanning. As with any autologous labeled biologic agent,
radiopharmaceuticals exhibit varying degrees of nonspeci- extreme care must be taken to maintain the integrity of the
ficity and are best used with meticulous clinical correlation. blood sample and to ensure that reinjection of the labeled
The particular effectiveness of each of the radiopharmaceu- leukocytes is performed only in the patient from whom
ticals for infection imaging often depends on the clinical the cells were taken. Clinical studies comparing 99mTc and
111
setting and the specific part of the body under scrutiny. In-leukocytes have not shown any intrinsic differences in
Selection of the proper imaging agent is critical to the sensitivity for infection when standard 24-hour imaging is
success of the procedure (Table 12.1). The commonly used performed. However, some notable differences between the
agents include the following: two radiopharmaceuticals make one or the other preferable
• Radiolabeled leukocytes in certain clinical situations.
• Indium-111 (111In) leukocytes
• Technetium-99m (99mTc) leukocytes Mechanism of Localization
• Gallium-67 (67Ga) citrate
• Fluorine-18 fluorodeoxyglucose (18F-FDG) Radiolabeled leukocytes are attracted to sites of inflamma-
Both computed tomography (CT) and magnetic resonance tion, where they are activated by local chemotactic factors
imaging (MRI) are also effective techniques and may be and pass from the bloodstream through the vascular endo-
preferable under certain circumstances. thelium into the soft tissues. The leukocytes then move
toward the site of inflammation in a directed migration
RADIOLABELED LEUKOCYTES called chemotaxis. If the inflammation has an infectious
cause, the labeled neutrophils phagocytize and destroy any
Leukocyte imaging using in vitro labeling with 111In-oxine offending bacteria. Gamma camera imaging localizes these
or 99mTc-exametazime is currently the nuclear medicine gold accumulations of radiolabeled leukocytes and thus reveals
standard for diagnosing most infections in patients who are the site of inflammation or infection. Like gallium uptake,
not immunocompromised. Because leukocytes can be sepa- radiolabeled leukocyte uptake is not specific for infection
rated and labeled without significant loss of function, they and may occur in any inflammatory process that incites a
can be used to image inflammatory processes. Both 111In- leukocyte response. Occasional uptake in neoplasms may be
oxine leukocytes and 99mTc-hexamethylpropyleneamine noted.
362
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CHAPTER 12 Inflammation and Infection Imaging 363
TABLE
12.1 Infection Imaging Radiopharmaceuticals
Radiopharmaceutical
and Administered Time of
Activity Imaging Advantages Disadvantages Common Uses
111
In white blood cells 12–24 hr No interfering bowel/ Less sensitivity for Bacterial infections
300–500 µCi renal activity nonbacterial and Indolent inflammatory conditions (e.g.,
(11.1–18.5 MBq) Delayed imaging nonpyogenic infections prosthetic joint infections)
111
possible In label not ideal for Abdominal infections
Simultaneous imaging Prosthetic vascular graft infections
99m
Tc-sulfur colloid Complex preparation Brain abscess
or 99mTc- Low sensitivity for discitis Complicated osteomyelitis
diphosphonate Extremity infections (e.g., diabetic foot)
bone imaging Renal infections
possible FUO: acute phase
99m
Tc-white blood cells 0.5–4.0 hr Early imaging Less sensitivity for Bacterial infections
5–10 mCi (185–370 Excellent early nonbacterial and Acute inflammatory conditions (e.g.,
MBq) sensitivity nonpyogenic infections inflammatory bowel disease)
99m
Tc label ideal for Delayed imaging not Complicated osteomyelitis
imaging ideal Extremity infections: diabetic foot
Early renal activity Osteomyelitis
Bowel activity after 1–2 Prosthetic vascular graft infections
hours
Complex preparation
Low sensitivity for discitis
67
Ga-citrate 5–10 mCi 24–48 hr A variety of Interfering bowel and Immunocompromised patients
(185–370 MBq) infections renal activity Chronic infections
detected, Delayed imaging Discitis/spinal osteomyelitis
including necessary FUO: chronic phase
67
opportunistic Ga not ideal for
imaging
18
F-FDG PET/CT 1–2 hr Excellent spatial Not currently FDA Sarcoidosis
5-10 mCi (185- localization approved for infections Peripheral bone osteomyelitis (not
370 MBq) Very sensitive Nonspecific; also diabetic or postoperative)
localizes in tumors Non-postoperative spinal infection
FUO
Metastatic infection
Primary vasculitis
CT, Computed tomography; FDA, US Food and Drug Administration; 18F-FDG, fluorine-18 fluorodeoxyglucose; FUO, fever of unknown origin; 111In, indium-111;
67
GA, gallium-67; PET, positron emission tomography; 99mTc, technetium-99m.
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364 C HA P T E R 1 2
364 Inflammation and Infection Imaging
intravenously. Care should be taken to avoid excessive agita- prominent accumulation, significantly more than that in
tion of the leukocytes because this may cause clumping, the liver. No renal or bowel activity is normally present.
resulting in focal lung accumulation. Although some Damaged leukocytes that remain labeled may provide
abscesses can be detected in the first few hours after the increased activity in the liver, if slightly damaged, and
administration of labeled leukocytes, most imaging is per- increased lung activity if severely damaged.
formed 18 to 24 hours after administration. If the urgency
of the clinical setting dictates, 4- to 6-hour images may be
Clinical Applications
useful. A whole-body scan can be performed by using a
medium-energy collimator, with gamma camera spot images General Considerations
obtained of specific areas of interest as needed. Generally, Indium-111 leukocytes are taken up nonspecifically at sites
both the 173- and 247-keV gamma emissions of 111In are of inflammation that incite a leukocytic response regardless
used. A sample imaging protocol and radiation dosimetry of the presence or absence of infection (Box 12.1). The
are presented in Appendix E. sensitivity (90%) and specificity (90%) are greatest for acute
pyogenic infections of less than 2 to 3 weeks’ duration,
Normal Scan when leukocytes are still rapidly accumulating. Their effec-
tiveness for detecting more chronic infections is somewhat
In the first few hours after administration of 111In-leukocytes, controversial, although sensitivity with mixed cell popula-
activity is noted in the lungs (likely as a result of leukocyte tions, which include lymphocytes and chronic inflamma-
activation), liver, spleen, and blood pool. The lung and tory cells as well as neutrophils, generally appears high (80%
blood pool activity decreases during the first few hours as to 85%). This may also be because some common bacterial
spleen and liver activity increases. By 18 hours, no lung or infections may demonstrate significant levels of neutrophil
blood pool activity is detected, but bone marrow activity is infiltration for months. Labeled leukocytes are of no use
noted (Fig. 12.1). in the detection of viral and parasitic infections. Factors
Twenty-four hours after administration, the 111In- that can theoretically reduce leukocyte function, including
leukocyte preparation may be found in the liver, spleen, and antibiotics, steroids, chemotherapeutic agents, hemodialy-
bone marrow, with the spleen providing the most sis, hyperalimentation, and hyperglycemia, do not appear
• Fig. 12.1 Normal Indium-111 Leukocyte Scan. (Left) Anterior and (right) posterior images demonstrate
liver and splenic activity. The splenic activity normally is greater. A small amount of bone marrow activity
is also identified.
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CHAPTER 12 Inflammation and Infection Imaging 365
to diminish labeled leukocyte sensitivity for detecting intense the bowel activity compared with liver activity, the
infection. more likely it is to indicate a true positive study.
Indium-labeled leukocytes are the preferred radiophar- Normal transient physiologic lung activity on early
maceutical for imaging abdominal infection, although in images (1 to 4 hours) severely limits usefulness of 111In-
practice, CT scans are usually the initial imaging study leukocytes in evaluating pulmonary abnormalities. Increased
ordered for abdominal pain or suspected infection. Because lung activity is of low specificity at 24 hours as well, because
of the lack of normal bowel activity, 111In-labeled leukocytes it may occur in numerous infectious and noninfectious
have a significant advantage over 99mTc-labeled leukocytes processes, including atelectasis, congestive heart failure, pul-
in diagnosing abdominal abscesses with high sensitivity monary emboli, aspiration, pneumonia, and adult respira-
(85% to 95%). The presence of considerable hepatic and tory distress syndrome. Only one-third of patients showing
especially splenic activity may hamper the detection of focal or diffuse uptake in the lungs have infectious causes,
infection in the upper abdomen. Splenic bed abscesses with although focal uptake demonstrates a slightly better correla-
intense activity may even be confused with a normal spleen tion with infection.
(Fig. 12.2), although CT usually resolves this issue. Uncom-
plicated pancreatitis is usually negative, but septic complica- Fever of Unknown Origin (Occult Fever)
tions are often imaged successfully. In a genuine fever of unknown origin (FUO), the spec-
Labeled leukocyte activity in the gastrointestinal tract is trum of possible pathology is extensive. The three major
nonspecific and may indicate a number of pathologies, categories that account for most FUO are infections,
including Crohn disease, ulcerative colitis (Fig. 12.3), pseu- malignancies, and noninfectious inflammatory disease. In
domembranous colitis, diverticulitis, various gastrointestinal occult fevers with a strong suggestion of a pyogenic cause,
infections, fistulas, ischemic or infarcted bowel, and even leukocyte scans may be the study of choice when CT or
vigorous enemas administered before imaging. Increased other anatomic imaging procedures cannot localize the
activity in the bowel, especially the colon, may also be disease. However, there is evidence indicating that posi-
problematic in that activity may be found in the absence of tron emission tomography (PET)/CT with 18F-FDG,
true gastrointestinal disease. False-positive bowel activity is although not specific for infection, may be the most effi-
generally caused by swallowing of leukocytes in patients cient method for evaluation of FUO. The value of either
18
with endotracheal or nasoesophageal tubes, respiratory tract F-FDG or 67Ga scanning in FUO is the ability to detect
infections, sinusitis, or pharyngitis or in patients with the spectrum of causative pathologies rather than just
gastrointestinal bleeding of any cause. In general, the more infection.
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366 C HA P T E R 1 2
366 Inflammation and Infection Imaging
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CHAPTER 12 Inflammation and Infection Imaging 367
distribution may produce confusing foci of increased activ- photopenia, although suspicious for infection, is nonspe-
ity at a site of suspected infection owing to regionally cific and may be seen in numerous other entities, including
increased marrow uptake. Such false-positive results in the tumor, compression fracture, avascular necrosis, radiation
marrow-bearing skeleton can be avoided by performing therapy, Paget disease, fibrous dysplasia, and myelofibro-
marrow imaging with 99mTc-sulfur colloid simultaneously sis. In the setting of spinal infections, 18F-FDG PET/CT
(obtained using the different photopeaks of 99mTc and 111In)
for comparison with labeled leukocyte distribution.
Technetium-99m colloid activity 1 hour after injection is
compared with 111In-leukocyte activity at 24 hours in the
area of interest. Criteria for a positive study are (1) spatial
incongruence (i.e., leukocyte activity in the absence of
sulfur colloid activity) or (2) incongruence of intensity of
activity (i.e., leukocyte activity considerably greater than
corresponding colloid activity) (Fig. 12.4). Throughout the
skeleton, false-positive results may also be produced by non-
specific uptake of labeled leukocytes in recent fractures, R L
heterotopic bone formation, recent radiation therapy, some
neoplasms, and noninfectious inflammation, including that
caused by gout and rheumatoid arthritis. Simultaneous
bone scans may be valuable in leukocyte imaging of the
hands and feet to provide anatomic detail needed to sepa-
rate soft tissue from bony activity.
Osteomyelitis
In uncomplicated acute osteomyelitis, especially with
normal radiographs, a positive three-phase bone scan is
definitive in most settings and obviates the need for further
imaging with labeled leukocytes or MRI. Use of planar
99m
Tc-methylene diphosphonate (MDP) for osteomyeli- R L
tis has a sensitivity of greater than 80% and a limited
specificity of about 50%. The specificity increases to more
than 80% with use of single-photon emission computed
tomography (SPECT)/CT. White blood cell (WBC)
scanning has sensitivity and specificity above 90% and
18
F-FDG is reported to have a sensitivity of about 95%
and a specificity of about 85%. Chronicity of infection
does not appear to have a significant effect on sensitivity • Fig. 12.4 Expanded Marrow. In this patient who has had a right knee
of leukocyte imaging, although false-negative results have joint replacement, there is a possibility of infection or loosening of the
occurred. Indium-111 leukocytes, however, have low sen- prosthesis. (Top) Anterior view of an indium-111 (111In) leukocyte scan
sitivity for spine infections, including osteomyelitis and over both knees shows asymmetric activity extending distal to the right
knee joint. (Bottom) Technetium-99m colloid scan over both knees
discitis. For uncertain reasons, more than half of spine demonstrates marrow activity, indicating, in this case, asymmetrically
infections appear as photopenic (cold) defects in the areas of expanded marrow. The pattern of 111In leukocyte uptake is thus con-
involvement rather than as hot spots (Fig. 12.5). This focal cordant with the marrow distribution and does not indicate infection.
L R L R
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368 C HA P T E R 1 2
368 Inflammation and Infection Imaging
or 67Ga is preferred. In the clinical circumstance of sus- activity. Leukocyte scans in this setting have an overall
pected osseous infection complicating disturbed or diseased accuracy of about 80%.
bone in which radiographs and 99mTc-diphosphonate bone
imaging are likely to be abnormal and nonspecific, 111In- Neuropathic Joint Infections
leukocytes provide an accurate tool to unmask or rule out Infections may commonly complicate neuropathic joints.
osteomyelitis. However, in early, rapidly progressing sterile neuropathia,
both bone scans and 111In-leukocyte scans are frequently
Posttraumatic Infections positive because of associated inflammatory and destruc-
Indium leukocyte scans may be positive for several weeks tive bony changes. Thus the findings on leukocyte and
in recent fractures in the absence of superimposed infection, bone imaging may be indistinguishable from osteomyelitis.
although the uptake is usually faint. Intense focal uptake at Faint, diffuse leukocyte activity that fades between the 4-
a site of suspected osteomyelitis is indicative of bony infec- and 24-hour images is suggestive of sterile disease, whereas
tion. In this setting, sensitivity and specificity rates exceed more intense focal activity that is distinctly different in
90%, which are significantly better than the rates for gallium distribution from the bone scan activity and that increases
imaging (50% to 60%). over time suggests superimposed infection. In chronic forms
of neuropathic osteoarthropathy, interpretation of the leu-
Prosthetic Joint Infections kocyte and bone scans is simplified by the less avid inflam-
Combined leukocyte/marrow imaging is the radionuclide matory response and decreased soft-tissue background
imaging procedure of choice for diagnosing prosthetic joint activity.
infection. Painful prosthetic joints may be attributable to
loosening or infection. Bone scans may be falsely positive Active Arthritis
during the first year after surgery, owing to healing and Arthritides, even those normally of a chronic nature, can
bony remodeling, especially in the hip or knee. Although have tremendous leukocyte responses. Thus leukocyte scans
111
In-leukocytes are very sensitive for periprosthetic infec- have been applied to diagnosing and monitoring the activity
tions, because labeled leukocytes may accumulate in the of rheumatoid arthritis. In this setting, 99mTc-labeled leuko-
normal bone marrow adjacent to a prosthesis, including cytes show early positivity, improved image quality, and
marrow in heterotopic bone formation, false-positive results decreased radiation exposure compared with that of 111In-
may occur. To increase accuracy, the procedure of choice in labeled leukocytes.
this setting is a 111In-leukocyte scan accompanied by 99mTc–
sulfur colloid marrow imaging. The sulfur colloid study Vascular Graft Infection
provides a map of postsurgical marrow distribution, whereas Perigraft gas on a CT scan is strongly suggestive of infection;
the leukocytes map both the distribution of marrow and however, this is seen in only 50% of cases. In the setting of
any accompanying infection. Thus congruent images indi- a negative or equivocal CT scan, 111In-leukocytes are useful
cate that leukocyte uptake is likely related to normal marrow in detecting vascular graft infections, including infections
activity, whereas areas that concentrate leukocytes but not of dialysis access grafts. More than 90% of patients with
sulfur colloid indicate areas of infection. This combined positive scans have subsequently documented culture evi-
study has a sensitivity and accuracy in excess of 90%. In the dence of infection (Fig. 12.6). Causes of false-positive
hip, labeled leukocyte activity over the head of the prosthe- results are perigraft hematomas, graft thrombosis, and graft
sis is strongly suggestive of infection, whereas activity in the epithelialization, which occurs in the first several weeks after
region of the shank is less so because of a plug of normal surgery. Use of 18F-FDG for evaluation of vascular grafts is
marrow that may be pushed to the tip of the prosthesis discussed later in this chapter.
when inserted.
Diabetic Foot Infections
Technetium-99m HMPAO Leukocytes
MRI is the procedure of choice for diabetic pedal infec- The role of 99mTc-HMPAO leukocytes in inflammation
tions, although labeled leukocytes can be helpful if the imaging can be better appreciated by a comparison with
111
diagnosis remains uncertain. Labeled leukocyte activity in In-leukocytes. Although they are similar in many respects,
normal bone marrow does not usually cause a problem in there are a few important differences:
interpretation of images in the peripheral skeleton. Uptake • The technetium label permits higher administered activ-
of labeled leukocytes in adjacent ulcers or cellulitis, ity, which improves visualization of small-part anatomy
however, along with decreased resolution of anatomic such as the hands and feet.
detail using the 111In label, may confound separation of • The shorter 6-hour half-life of 99mTc limits delayed
soft tissue from bony uptake, especially in the hands and imaging, which can be important for optimal accumula-
feet. In this setting, comparison of a simultaneous bone tion of labeled leukocytes in more indolent processes.
scan (obtained on a separate photopeak) with the 111In- • Technetium-99m HMPAO leukocyte preparations
leukocyte distribution may provide the anatomic informa- display normal gastrointestinal tract, urinary tract, and
tion needed to distinguish between bone and soft-tissue gallbladder activity.
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CHAPTER 12 Inflammation and Infection Imaging 369
Normal Distribution
Indium-111 and 99mTc-leukocytes display identical bioki-
netics in the liver, spleen, and lung. Unlike 111In-leukocytes,
however, which show increasing bone marrow activity over
24 hours with constant activity thereafter, 99mTc-leukocyte
activity in bone marrow increases over the first 3 hours after
injection but decreases over the next 24 hours. In addition,
unbound 99mTc-HMPAO complexes from the leukocyte
preparation are seen in the gastrointestinal tract, kidneys,
• Fig. 12.6 Graft Infection. In this patient who was on renal dialysis, and bladder and occasionally in the gallbladder. Bowel
an infection of the dialysis graft was suspected. Technetium-99m activity is likely related to biliary excretion. Renal activity
leukocyte scan demonstrates normally expected activity in the bone
marrow of the humerus and proximal forearm, but there is also mark-
is primarily attributable to urinary excretion, with a variable
edly increased activity extending throughout and proximal to the graft amount of parenchymal binding.
site (arrows).
Clinical Applications
• There is faster accumulation of sufficient 99mTc-HMPAO Thorax
leukocytes in sites of infection to permit earlier imaging. Similar to their 111In-labeled counterparts, 99mTc-leukocytes
• Lower absorbed doses (compared with 111In-leukocytes) localize nonspecifically in lung inflammation or infection
enhance suitability for imaging infants and children. and play a limited role in chest disease. Uptake may be seen
Otherwise, 99mTc-HMPAO leukocytes share most of the in pneumonias, systemic vasculitis, adult respiratory distress
other advantages and disadvantages of 111In-leukocytes. syndrome, Pneumocystis carinii (jirovecii) pneumonia (PCP),
or drug-induced pneumonitis. In bronchiectasis, preopera-
Labeling tive 99mTc-leukocyte imaging may be used to determine
which lesions noted on CT are actively inflamed.
The circulating granulocyte count should be a minimum of
2 × 106 cells/mL. The labeling process is similar in principle Abdomen/Pelvis
to that used in the 111In-oxine procedure. A 99mTc-HMPAO Early images for localization of abdominopelvic abscesses
lipophilic complex enters the separated leukocytes and is are sensitive because of the rapid accumulation of 99mTc-
converted to a hydrophilic form, which is trapped inside the leukocytes in pyogenic foci. Sequential imaging at 1 and 4
cells. The efficiency of this technetium label is less than that hours may be useful to differentiate abnormal leukocyte
of indium. Unlike 111In-oxine, which labels a mixed popula- accumulations from nonspecific bowel activity and to avoid
tion of cells, HMPAO preferentially labels neutrophils. false-positive results caused by imaging at 4 hours only. For
inflammatory bowel disease, 1-hour information with 99mTc
Technique is comparable to that seen on 3-hour 111In images, with
99m
Tc providing better visualization in the small bowel.
Between 5 and 10 mCi (185 to 370 MBq) of 99mTc- Bowel segments showing increased activity at 1 hour that
HMPAO leukocytes are intravenously injected in adult increase in activity at 4 hours provide a higher specificity of
patients. The administered activity for children is 0.1 to diagnosis than does activity appearing for the first time at
0.2 mCi/kg (3.7 to 7.4 MBq/kg), with a minimum of 4 hours or remaining at the same intensity. Technetium-
0.5 mCi (18 MBq). Technetium-99m leukocytes localize in 99m leukocytes can be used to establish a diagnosis, identify
sites of infection more rapidly than do 111In-oxine leuko- diseased segments, confirm relapse, identify complications
cytes, with a maximal sensitivity at 30 minutes. The imaging of Crohn disease such as mural abscess, and quantify disease.
sequence depends on the clinical setting. Early whole-body The distribution of activity in the colon allows a distinction
and/or spot images are usually acquired at 0.5 to 4 hours, between Crohn disease and ulcerative colitis with a high
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370 C HA P T E R 1 2
370 Inflammation and Infection Imaging
degree of certainty. Rectal sparing, small bowel involve- Abdominal and Retroperitoneal
ment, and “skip” areas suggest Crohn disease, whereas con- Inflammation and Infection
tinuous involvement from the rectum without small bowel
involvement suggests ulcerative colitis. A false-positive In general, the proper interpretation of gallium images in
appearance on early images may be caused by oozing from the abdomen hinges on the differentiation of physiologic
recent anastomoses or active gastrointestinal bleeding. With activity from abnormal accumulations of the radiopharma-
99m
Tc-leukocytes, renal infections and hepatobiliary sepsis ceutical. A common problem in image interpretation in the
may be difficult to distinguish from physiologic activity, and abdomen is the presence of gallium in the bowel, which
111
In-labeled leukocytes may be preferable in these may mimic lesions or mask disease. Bowel activity is par-
settings. ticularly prominent in the colon and may be diffuse or focal.
Frequently, activity is seen in the regions of the cecum,
hepatic and splenic flexures, and rectosigmoid. These accu-
GALLIUM IMAGING mulations may appear as early as a few hours after injection.
The progress of excreted gallium through the colon over
Mechanism of Localization time may provide the best evidence of physiologic activity,
whereas persistence of gallium in a given area of the abdomen
Use of 67Ga citrate has largely been supplanted by other tech- should be viewed as abnormal.
niques for imaging of infection and neoplasms. Gallium-67 Persistence of more than faint renal activity after 24
imaging accumulates nonspecifically in inflammatory and hours, progressively increasing activity, and unilateral dis-
infectious diseases, as well as neoplastic diseases. crepancy in gallium activity in the kidneys should be con-
The mechanisms of gallium citrate localization in inflam- sidered abnormal. However, abnormally increased activity
matory tissues are likely different in some respects from the in one or both kidneys can occur in nonspecific patho-
mechanisms associated with localization in neoplasms. The logic and physiologic states and may therefore present a
process is complex, but a few basic principles are known to difficult problem of differential diagnosis. The differential
be associated with such concentration: (1) gallium binds includes urinary obstruction, nephritis, acute tubular necro-
with the plasma transport protein transferrin that acts as a sis, diffuse infiltrative neoplasm, vasculitis, parenteral iron
carrier for 67Ga to sites of inflammation; (2) gallium is also injections, blood transfusions, and perirenal inflammatory
incorporated into leukocytes, bound by intracellular lacto- disease.
ferrin, which then migrate to inflamed areas; and (3) gallium
is also taken up by pathogenic microorganisms themselves Fever of Unknown Origin
by binding to siderophores produced by the bacteria.
Initial imaging for an FUO should begin with labeled leu-
Technique kocytes or CT scan and followed with an 18F-FDG CT or
gallium study, if necessary. Although gallium is reasonably
The uptake of 67Ga citrate is relatively slow in suspected sensitive for localized pyogenic disease (80% to 90%), it is
infection, so imaging is usually performed 18 to 24 hours less sensitive than are radiolabeled leukocytes, especially in
after injection, with further delayed images obtained as the abdomen, where about one-third of infections respon-
needed. Suggested imaging protocol and dosimetry are pre- sible for FUO are found.
sented in Appendix E.
Immunocompromised Patients
Normal Distribution
Because its sensitivity for detection of infection does not
Early clearance of gallium by the kidneys results in their faint depend on acute pyogenic response, gallium imaging can
visualization at 24 hours, at which time activity is most promi- sometimes be a useful radionuclide procedure for detecting
nent in the liver and to a lesser degree in the bone marrow and evaluating the varied opportunistic pulmonary infec-
and spleen. Activity in the salivary and lacrimal glands, naso- tions and adenopathies common in patients with compro-
pharynx, and breasts is variable. Gallium is also excreted by mised immune systems resulting from acquired immune
the colon, which can interfere with imaging inflammatory or deficiency syndrome (AIDS), antineoplastic chemotherapy,
infectious processes in the abdomen and pelvis. or immunosuppression after organ transplantation.
In immunocompromised patients, gallium scans of the
Clinical Applications thorax should always be interpreted in comparison with
recent chest radiographs, which add specificity to the exami-
The significance of an abnormal accumulation of gallium nation. A normal gallium scan with a normal chest radio-
increases with the intensity of the focus as seen on appropri- graph essentially excludes an infectious process. A normal
ate images. In general, however, any abnormal gallium gallium scan in the presence of a focal mass or infiltrate on
activity equal to or greater than that seen in the liver may the chest radiograph, however, suggests the diagnosis of
be considered significant. Kaposi sarcoma, which does not accumulate gallium.
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CHAPTER 12 Inflammation and Infection Imaging 371
• Fig. 12.7 Pneumocystis Pneumonia. (Left) Anterior and (right) posterior 24-hour gallium images dem-
onstrate normal physiologic excretion in the colon; however, there is markedly abnormal increased activity
in both lungs. Note the negative cardiac defect produced by the intense lung activity.
Bilateral intense diffuse homogeneous pulmonary uptake of avium-intracellulare are usually gallium-positive and thallium-
gallium is the classic appearance of PCP and occurs in 60% negative but may show faint thallium uptake.
to 70% of cases. The gallium scan is frequently positive
before chest radiographs become abnormal. The specificity Osteomyelitis
of a diffusely positive scan is greater when the chest radio-
graph is negative and the pulmonary activity is intense The initial imaging test of choice for osteomyelitis is a
(equal to or greater than liver activity) (Fig. 12.7). routine radiograph. If this is negative, triple-phase bone
Successful treatment of PCP is generally reflected by imaging with 99mTc-diphosphonates combined with leuko-
decreasing intensity of gallium uptake or a return to a normal cyte imaging is the radionuclide procedure of choice for the
appearance. In patients with AIDS, lymph node involve- diagnosis of uncomplicated osteomyelitis, with a sensitivity
ment by a variety of diseases is common. Gallium uptake in of greater than 90%. In some circumstances, such as sus-
the generalized lymphadenopathy associated with AIDS and pected infection, complicating trauma, postsurgical hard-
AIDS-related complex is variable in occurrence and degree ware placement, or other underlying bone disease, gallium
of activity, which may be minimal. Increased gallium uptake imaging may increase the specificity of a positive bone scan
equal to or greater than liver activity in hilar, mediastinal, and suggest the presence of osteomyelitis. In these settings,
periaortic, or supraclavicular nodes suggests the diagnoses of the following apply:
malignant lymphoma, Mycobacterium tuberculosis, or Myco- • Osteomyelitis is likely if the intensity of gallium activity
bacterium avium-intracellulare. However, this nodal activity exceeds bone scan activity in the same location (spatially
is nonspecific, and other less common infectious processes congruent images) or when the spatial distribution of
cannot be excluded. gallium exceeds that of the bone scan (spatially incongru-
In the abdomen, abnormal gallium accumulation may be ent images).
seen in bacterial abscess and gastrointestinal infections, as well • Osteomyelitis is unlikely if gallium images are normal,
as in regional lymph nodes affected by M. avium-intracellulare regardless of bone scan findings or when gallium distri-
or lymphoma. Combined imaging with thallium-201 (201Tl) bution is less than bone scan activity on spatially incon-
and 67Ga may add to the diagnostic specificity of gallium gruent images.
imaging in the setting of immunocompromised patients. • Because gallium is a weak bone agent in addition to
With some exceptions, this type of combined imaging has being an inflammatory marker, a gallium scan may be
yielded the following results. Kaposi sarcoma is gallium- considered nondiagnostic for osteomyelitis when the dis-
negative but thallium-positive. Lymphoma is both gallium- tribution and activity of the gallium and bone scan activ-
and thallium-positive. Acute infections, tuberculosis, and M. ity are the same.
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372 C HA P T E R 1 2
372 Inflammation and Infection Imaging
Gallium is also useful in conjunction with bone scans in the “panda sign,” produced by symmetric increase in activity
diagnosis of spinal infections (discitis, osteomyelitis), in in the lacrimal, parotid, and salivary glands, represents a
which labeled-leukocyte has low-sensitivity imaging with a highly specific pattern for sarcoidosis (Fig. 12.8). Simi-
high false-negative rate. larly, the panda sign by itself is not specific and may be
seen in a significant percentage of patients with radiation
Sarcoidosis sialoadenitis, primary Sjögren syndrome, and in patients
with AIDS.
The lesions of active sarcoidosis are quite gallium-avid, In the presence of gallium-avid adenopathy in the medi-
especially in the chest. Cardiac, nodal, and parenchymal astinal and hilar regions, the diagnosis of lymphoma or
lung involvement can be detected. In the early stages, infectious disease, especially in human immunodeficiency
gallium images are frequently positive before any radio- virus (HIV)-positive patients, must also be considered. In
graphic abnormalities are noted. The finding of increased malignant lymphomas, however, the adenopathy is fre-
gallium or FDG activity in intrathoracic lymph nodes quently asymmetric.
(right paratracheal and hilar) in a pattern resembling In the later stages of sarcoid lung disease, a diffuse
the Greek letter lambda (λ) is suggestive of sarcoidosis. increase in lung activity with or without gallium-avid ade-
However, a lambda sign in combination with a so-called nopathy is common. In this setting, gallium can be used to
A B
• Fig. 12.8 Sarcoidosis. (A and B) Forty-eight-hour anterior and lateral images of the head and neck
from a gallium-67 scan in this 25-year-old woman show symmetrically increased activity in the parotid
glands, salivary glands, and lacrimal glands (panda sign). (C) Gallium-67 scan in a different patient
also shows the lambda sign of lymph nodes in the mediastinum as well as a panda sign. Either sign
alone is suggestive of sarcoidosis, but together they offer high specificity for the diagnosis. Note also
C
the active inguinal nodes.
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CHAPTER 12 Inflammation and Infection Imaging 373
distinguish active parenchymal disease from inactive sar- an infectious cause of FUO, 111In-leukocytes are often pre-
coidosis or chronic fibrosis. Diffuse increased activity (equal ferred because of their high specificity for an infectious
or greater than liver activity) correlates with active disease, etiology. In patients with noninfectious inflammatory dis-
whereas normal lung activity (equal to soft-tissue back- eases, 18F-FDG PET seems to be valuable in detecting or
ground activity) is compatible with remission. In extensive managing diseases, such as inflammatory bowel disease,
sarcoidosis, periaortic, retroperitoneal, and pelvic nodal large vessel vasculitis, autoimmune diseases, acute respira-
activity may be seen, but this is more commonly found in tory distress syndrome, asthma, idiopathic interstitial pneu-
patients with lymphoma. monia, and sarcoidosis. With respect to neoplastic causes
of FUO, Hodgkin disease, aggressive non-Hodgkin lym-
phoma, colorectal cancer, and sarcomas are usually readily
FLUORINE-18 FLUORODEOXYGLUCOSE detected. Whatever the setting, it should be remembered
PET/CT IMAGING that 18F-FDG uptake is nonspecific and cannot reliably
distinguish a benign inflammatory process, such as lung
Mechanism of Localization abscess or pneumonia (Fig. 12.9), from lung cancer.
A B
• Fig. 12.9 Pneumonia. (A) Computed tomography (CT) scan of the chest demonstrates an alveolar
infiltrate in the left lower lobe. (B) Fluorine-18 fluorodeoxyglucose positron emission tomography/CT scan
shows increased metabolic activity in the pneumonia.
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374 C HA P T E R 1 2
374 Inflammation and Infection Imaging
C
• Fig. 12.10 Active Tuberculosis. (A) Chest radiograph shows hyperinflation (chronic obstructive pulmo-
nary disease) but also a right upper lobe cavitary infiltrate with hilar and mediastinal retraction. (B) Chest
computed tomography (CT) confirms the findings but is unable to assess activity. (C) Fluorine-18 fluoro-
deoxyglucose positron emission tomography/CT fusion image shows increased metabolic activity.
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CHAPTER 12 Inflammation and Infection Imaging 375
Transverse
Sagittal Coronal
tomography fusion images show increased activity in both right and left upper lung zones.
• Fig. 12.12 Inactive Granuloma. (Left) A solitary pulmonary nodule (arrow) was identified on chest
radiograph. Computed tomography (CT) scan shows the nodule to be noncalcified. (Right) Fluorine-18
fluorodeoxyglucose positron emission tomography/CT image does not show any metabolic activity
(arrow). An active granuloma can have uptake and would not be possible to differentiate from a
malignancy.
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376 C HA P T E R 1 2
376 Inflammation and Infection Imaging
B C D
• Fig. 12.13 Hepatic Abscess. (A) Computed tomography (CT) scan shows two areas of irregularly
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CHAPTER 12 Inflammation and Infection Imaging 377
A B
C D E
• Fig. 12.14 Ulcerative Colitis. (A) Lateral maximum intensity projection positron emission tomography
(PET) image shows increased activity in the rectum and rectosigmoid (arrow). (B) Computed tomography
(CT) scan shows bowel wall thickening, and (C–E) fluorine-18 fluorodeoxyglucose PET/CT images show
increased activity.
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B
A C
• Fig. 12.16 Infected Central Catheter. (A) Radiograph shows a chemotherapy catheter suspected of
being infected. (B) Chest computed tomography (CT) shows the catheter tip in the superior vena cava.
(C) Fluorine-18 fluorodeoxyglucose positron emission tomography/CT image shows markedly increased
activity.
A B
C D E
• Fig. 12.17 Mycotic Abdominal Aortic Aneurysm. (A) Anterior maximum intensity projection positron
emission tomography (PET) image shows an abnormal focus of increased activity in the central abdomen
(arrow). (B) Contrasted computed tomography (CT) scan shows contrast filling a focal abdominal aortic
aneurysm (arrow). (C–E) Fluorine-18 fluorodeoxyglucose PET/CT images show increased metabolic activ-
ity in the mycotic aneurysm.
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CHAPTER 12 Inflammation and Infection Imaging 379
A B
• Fig. 12.19 Osteomyelitis of the Ischium. (A) Computed tomography (CT) scan of the lower pelvis shows
bone erosion of the ischium (arrow) and surrounding stranding edema. (B) Fluorine-18 fluorodeoxyglucose
positron emission tomography/CT image shows increased metabolic activity within the bone (arrow).
67
arthritis, radiation therapy (up to 2 years), and HIV- Ga-citrate imaging for chronic osteomyelitis (Fig. 12.19).
associated adenopathy (Fig. 12.18). A negative 18F-FDG scan can be very helpful in excluding
chronic osteomyelitis. Although both cellulitis and osteo-
Central Nervous System myelitis demonstrate increased activity, these can often be
differentiated by the anatomic localization afforded by
The differentiation of primary central nervous system (CNS) PET/CT or PET/MRI, as well as by any diagnostic bony
lymphoma and nonmalignant lesions due to opportunistic changes revealed on CT. Septic or active inflammatory
infections is crucial because of the different treatments arthritis is also associated with increased uptake (Fig. 12.20).
involved. One specific setting in which 18F-FDG is helpful However, 18F-FDG does not appear to offer any advantage
is to distinguish CNS lymphoma (metabolically active and over labeled white cells for differentiating infected joint
thallium-positive) from CNS toxoplasmosis (not metaboli- prostheses from aseptic loosening. MRI is the procedure of
cally active and thallium-negative) in patients with AIDS. choice for suspected diabetic foot infections.
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380 C HA P T E R 1 2
380 Inflammation and Infection Imaging
B C
D E
• Fig. 12.20 Septic Arthritis. (A) Anterior maximum intensity projection positron emission tomography
(PET) image shows markedly increased activity about the right hip. (B and C) Computed tomography (CT)
scan shows mottled destruction of the right femoral head. (D and E) Corresponding fluorine-18 fluorode-
oxyglucose PET/CT images show the increased metabolic activity to be centered in the joint space.
fibrosis, and calcification to possible rupture. Studies have radiolabeled chemotactic and antimicrobial peptides with
shown that 18F-FDG imaging has shown promise in the a high affinity for inflammatory cells that bind in vivo to
diagnosis of a variety of vasculitides, as well as in the predic- both circulating granulocytes and those already present at
tion of future cardiovascular events. the site of inflammation have been identified as poten-
Suspected infection of pacemakers and catheters can be tial imaging agents. These include bacterial products that
evaluated using 18F-FDG with high sensitivity; however, initiate leukocyte chemotaxis by binding to high-affinity
usefulness in the evaluation of endocarditis, vascular pros- receptors on the surfaces of inflammatory cells. Other inter-
thetic infections, or aneurysm progression is as yet unde- esting approaches involve 99mTc multilamellar liposomes,
fined. Noninfected synthetic prosthetic vascular grafts can which are phagocytized by leukocytes at sites of inflam-
show homogenous or inhomogeneous uptake, which can mation, and 99mTc-labeled nanometer-sized human serum
remain unchanged for months or years. albumin colloids (nanocolloids), which leave the circulation
and enter the extravascular spaces because of discontinu-
FUTURE INFLAMMATION AGENTS ity of the vascular endothelium at sites of inflammation.
Inflammatory macrophages may also be imaged using PET
Potential new inflammation imaging agents include and SPECT ligands (e.g., dextran nanoparticles labeled
peptides, liposomes, and nanocolloids. A number of with zirconium-89).
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CHAPTER 12 Inflammation and Infection Imaging 381
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