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Inflammation and Infection Imaging


A variety of nuclear medicine imaging techniques provide effective methods for the detection and assessment of both clinically apparent and occult infectious and inflammatory conditions. Rather than representing organ-specific techniques, these procedures use radiopharmaceuticals that localize preferentially in inflamed or infected tissue in any location in the body. The available radiopharmaceuticals exhibit varying degrees of nonspecificity and are best used with meticulous clinical correlation. The particular effectiveness of each of the radiopharmaceuticals for infection imaging often depends on the clinical setting and the specific part of the body under scrutiny. Selection of the proper imaging agent is critical to the success of the procedure ( Table 12.1 ). The commonly used agents include the following:

  • Radiolabeled leukocytes

    • Indium-111 ( 111 In) leukocytes

    • Technetium-99m ( 99m Tc) leukocytes

  • Gallium-67 ( 67 Ga) citrate

  • Fluorine-18 fluorodeoxyglucose ( 18 F-FDG)

Both computed tomography (CT) and magnetic resonance imaging (MRI) are also effective techniques and may be preferable under certain circumstances.

TABLE 12.1
Infection Imaging Radiopharmaceuticals
Radiopharmaceutical and Administered Activity Time of Imaging Advantages Disadvantages Common Uses
111 In white blood cells 300–500 µCi (11.1–18.5 MBq) 12–24 hr No interfering bowel/renal activity
Delayed imaging possible
Simultaneous 99m Tc-sulfur colloid or 99m Tc-diphosphonate bone imaging possible		 Less sensitivity for nonbacterial and nonpyogenic infections
111 In label not ideal for imaging
Complex preparation
Low sensitivity for discitis		 Bacterial infections
Indolent inflammatory conditions (e.g., prosthetic joint infections)
Abdominal infections
Prosthetic vascular graft infections
Brain abscess
Complicated osteomyelitis
Extremity infections (e.g., diabetic foot)
Renal infections
FUO: acute phase
99m Tc-white blood cells 5–10 mCi (185–370 MBq) 0.5–4.0 hr Early imaging
Excellent early sensitivity
99m Tc label ideal for imaging		 Less sensitivity for nonbacterial and nonpyogenic infections
Delayed imaging not ideal
Early renal activity
Bowel activity after 1–2 hours
Complex preparation
Low sensitivity for discitis		 Bacterial infections
Acute inflammatory conditions (e.g., inflammatory bowel disease)
Complicated osteomyelitis
Extremity infections: diabetic foot
Osteomyelitis
Prosthetic vascular graft infections
67 Ga-citrate 5–10 mCi (185–370 MBq) 24–48 hr A variety of infections detected, including opportunistic Interfering bowel and renal activity
Delayed imaging necessary
67 Ga not ideal for imaging		 Immunocompromised patients
Chronic infections
Discitis/spinal osteomyelitis
FUO: chronic phase
18 F-FDG PET/CT 5-10 mCi (185-370 MBq) 1–2 hr Excellent spatial localization
Very sensitive		 Not currently FDA approved for infections
Nonspecific; also localizes in tumors		 Sarcoidosis
Peripheral bone osteomyelitis (not diabetic or postoperative)
Non-postoperative spinal infection
FUO
Metastatic infection
Primary vasculitis
CT , Computed tomography; FDA , US Food and Drug Administration; 18 F-FDG , fluorine-18 fluorodeoxyglucose; FUO , fever of unknown origin; 111 In , indium-111; 67 GA , gallium-67; PET , positron emission tomography; 99m Tc , technetium-99m.

Radiolabeled Leukocytes

Leukocyte imaging using in vitro labeling with 111 In-oxine or 99m Tc-exametazime is currently the nuclear medicine gold standard for diagnosing most infections in patients who are not immunocompromised. Because leukocytes can be separated and labeled without significant loss of function, they can be used to image inflammatory processes. Both 111 In-oxine leukocytes and 99m Tc-hexamethylpropyleneamine oxime (HMPAO) leukocytes have been shown to retain their innate function and have demonstrated relatively high sensitivity and specificity for acute infections. However, sensitivity may be somewhat lower for chronic infections. The procedure involves removing some of the patient's own leukocytes, labeling them, and reinjecting them before scanning. As with any autologous labeled biologic agent, extreme care must be taken to maintain the integrity of the blood sample and to ensure that reinjection of the labeled leukocytes is performed only in the patient from whom the cells were taken. Clinical studies comparing 99m Tc and 111 In-leukocytes have not shown any intrinsic differences in sensitivity for infection when standard 24-hour imaging is performed. However, some notable differences between the two radiopharmaceuticals make one or the other preferable in certain clinical situations.

Mechanism of Localization

Radiolabeled leukocytes are attracted to sites of inflammation, where they are activated by local chemotactic factors and pass from the bloodstream through the vascular endothelium into the soft tissues. The leukocytes then move toward the site of inflammation in a directed migration called chemotaxis . If the inflammation has an infectious cause, the labeled neutrophils phagocytize and destroy any offending bacteria. Gamma camera imaging localizes these accumulations of radiolabeled leukocytes and thus reveals the site of inflammation or infection. Like gallium uptake, radiolabeled leukocyte uptake is not specific for infection and may occur in any inflammatory process that incites a leukocyte response. Occasional uptake in neoplasms may be noted.

Indium-111 Oxine Leukocytes

Labeling Principle

Leukocyte imaging became possible after the development of successful methods for labeling leukocytes with 111 In-oxine. Indium-111 oxine labels all cell types indiscriminately, including platelets and red blood cells. Thus the leukocytes must be isolated from about 50 mL of anticoagulated blood before labeling, commonly through a process called gravity sedimentation , which simply consists of allowing the blood to sit for the time necessary for the red blood cells to settle to the bottom. Any red blood cells remaining in the supernatant may be either lysed by using hypotonic saline or ammonium chloride or removed by centrifugation.

Oxine forms a lipid-soluble complex with 111 In, which passively diffuses through the leukocyte cell membrane. Once this complex becomes intracellular, the 111 In separates from the oxine and binds to cytoplasmic components. The oxine then leaves the cell and is removed by washing the cells. A mixed population of leukocytes is usually labeled, although neutrophils constitute the majority. Labeling efficiencies are on the order of 95%. The patient's circulating granulocyte count should be at least 3 × 10 6 cells/mL to have enough cells to label.

Minimal manipulation of the leukocytes is essential during the labeling procedure to avoid damage to the cells, which could diminish their viability and thus limit their effectiveness as an imaging agent. Failure to preserve normal physiologic leukocyte function may result in false-negative imaging study results.

Technique

Approximately 300 to 500 µCi (11.1 to 18.5 MBq) of 111 In-oxine–labeled autologous leukocytes are administered intravenously. Care should be taken to avoid excessive agitation of the leukocytes because this may cause clumping, resulting in focal lung accumulation. Although some abscesses can be detected in the first few hours after the administration of labeled leukocytes, most imaging is performed 18 to 24 hours after administration. If the urgency of the clinical setting dictates, 4- to 6-hour images may be useful. A whole-body scan can be performed by using a medium-energy collimator, with gamma camera spot images obtained of specific areas of interest as needed. Generally, both the 173- and 247-keV gamma emissions of 111 In are used. A sample imaging protocol and radiation dosimetry are presented in Appendix E .

Normal Scan

In the first few hours after administration of 111 In-leukocytes, activity is noted in the lungs (likely as a result of leukocyte activation), liver, spleen, and blood pool. The lung and blood pool activity decreases during the first few hours as spleen and liver activity increases. By 18 hours, no lung or blood pool activity is detected, but bone marrow activity is noted ( Fig. 12.1 ).

Fig. 12.1, Normal Indium-111 Leukocyte Scan.

Twenty-four hours after administration, the 111 In-leukocyte preparation may be found in the liver, spleen, and bone marrow, with the spleen providing the most prominent accumulation, significantly more than that in the liver. No renal or bowel activity is normally present. Damaged leukocytes that remain labeled may provide increased activity in the liver, if slightly damaged, and increased lung activity if severely damaged.

Clinical Applications

General Considerations

Indium-111 leukocytes are taken up nonspecifically at sites of inflammation that incite a leukocytic response regardless of the presence or absence of infection ( Box 12.1 ). The sensitivity (90%) and specificity (90%) are greatest for acute pyogenic infections of less than 2 to 3 weeks' duration, when leukocytes are still rapidly accumulating. Their effectiveness for detecting more chronic infections is somewhat controversial, although sensitivity with mixed cell populations, which include lymphocytes and chronic inflammatory cells as well as neutrophils, generally appears high (80% to 85%). This may also be because some common bacterial infections may demonstrate significant levels of neutrophil infiltration for months. Labeled leukocytes are of no use in the detection of viral and parasitic infections. Factors that can theoretically reduce leukocyte function, including antibiotics, steroids, chemotherapeutic agents, hemodialysis, hyperalimentation, and hyperglycemia, do not appear to diminish labeled leukocyte sensitivity for detecting infection.

Box 12.1
Causes of Increased Activity on Labeled Leukocyte Images

Chest

Common Causes

  • Adult respiratory distress syndrome

  • Emphysema

  • Pleural tubes

  • Noninfected intravenous lines

  • Pneumonia

Uncommon Causes

  • Aspiration

  • Atelectasis

  • Cystic fibrosis

  • Graft infection

  • Herpes esophagitis

Abdomen

Common Causes

  • Enteric tubes

  • Ostomies

  • Phlegmon

  • Swallowed leukocytes

  • Wound infection

Uncommon Causes

  • Acute enteritis

  • Bowel infarction

  • Colitis

  • Crohn disease

  • Decubitus ulcer

  • Gastrointestinal bleeding

  • Graft infection

  • Pancreatitis

  • Transplant (with or without rejection)

  • Diverticulitis

  • Acute cholecystitis

Musculoskeletal and Skin Uptake

Common Causes

  • Intravenous site

  • Osteomyelitis

  • Sinusitis

Uncommon Causes

  • Lumbar puncture site

  • Rheumatoid arthritis

  • Septic arthritis

Any Body Part

  • Abscess

  • Cellulitis

  • Wound infection

  • Hematoma

  • Infected tumor

Indium-labeled leukocytes are the preferred radiopharmaceutical for imaging abdominal infection, although in practice, CT scans are usually the initial imaging study ordered for abdominal pain or suspected infection. Because of the lack of normal bowel activity, 111 In-labeled leukocytes have a significant advantage over 99m Tc-labeled leukocytes in diagnosing abdominal abscesses with high sensitivity (85% to 95%). The presence of considerable hepatic and especially splenic activity may hamper the detection of infection in the upper abdomen. Splenic bed abscesses with intense activity may even be confused with a normal spleen ( Fig. 12.2 ), although CT usually resolves this issue. Uncomplicated pancreatitis is usually negative, but septic complications are often imaged successfully.

Fig. 12.2, Postsplenectomy Abscess.

Labeled leukocyte activity in the gastrointestinal tract is nonspecific and may indicate a number of pathologies, including Crohn disease, ulcerative colitis ( Fig. 12.3 ), pseudomembranous colitis, diverticulitis, various gastrointestinal infections, fistulas, ischemic or infarcted bowel, and even vigorous enemas administered before imaging. Increased activity in the bowel, especially the colon, may also be problematic in that activity may be found in the absence of true gastrointestinal disease. False-positive bowel activity is generally caused by swallowing of leukocytes in patients with endotracheal or nasoesophageal tubes, respiratory tract infections, sinusitis, or pharyngitis or in patients with gastrointestinal bleeding of any cause. In general, the more intense the bowel activity compared with liver activity, the more likely it is to indicate a true positive study.

Fig. 12.3, Colitis.

Normal transient physiologic lung activity on early images (1 to 4 hours) severely limits usefulness of 111 In-leukocytes in evaluating pulmonary abnormalities. Increased lung activity is of low specificity at 24 hours as well, because it may occur in numerous infectious and noninfectious processes, including atelectasis, congestive heart failure, pulmonary emboli, aspiration, pneumonia, and adult respiratory distress syndrome. Only one-third of patients showing focal or diffuse uptake in the lungs have infectious causes, although focal uptake demonstrates a slightly better correlation with infection.

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