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Indium-111 White Blood Cell Scan
Introduction
Indium-111 (In-111)–labeled white blood cell (WBC) scintigraphy is a nuclear medicine imaging modality used to diagnose occult infections, especially when other imaging techniques are contraindicated or uninformative. This technique leverages the fundamental biological process in which labeled leukocytes migrate to and accumulate at sites of inflammation, which can then be visualized through nuclear imaging. Clinicians commonly use this test to evaluate suspected infections, including osteomyelitis, prosthetic joint infections, vascular graft infections, and fever of unknown origin (FUO). The clinical utility of In-111–labeled WBC scintigraphy varies significantly depending on the indication, with scans being more useful for evaluating osteomyelitis and vascular access infections, but less so for fevers of unknown origin. Notably, while In-111–labeled WBC scans can identify localized inflammation, they cannot distinguish between infectious and sterile inflammatory processes definitively. The technique primarily localizes areas of neutrophilic inflammation, which is highly suggestive of infection.
In contrast, conditions predominantly mediated by lymphocytes, such as tuberculosis, fungal infections, or sarcoidosis, often demonstrate little to no radiotracer accumulation. This distinction is critical, as false-negative results may occur in infections with minimal neutrophil recruitment. Multiple clinical series have reported wide sensitivities ranging from 43% to 100% and specificities ranging from 69% to 92% for infectious conditions.[1][2] A positive predictive value (PPV) of 0.92 and a negative predictive value (NPV) of 0.37 indicate that positive scans hold significantly more diagnostic weight than negative ones. Although some studies report high sensitivity for certain infections, In-111–labeled WBC scans are generally used as adjunctive tools rather than standalone tests. They may not offer sufficient diagnostic clarity in complex cases, particularly when challenging clinical decisions are involved.
The procedure involves obtaining a blood sample from the patient, isolating and labeling the WBCs with In-111 oxine, and then re-injecting the labeled cells intravenously. Subsequent imaging, typically performed 24 hours postinjection, reveals areas of In-111–labeled WBC accumulation, indicating sites of inflammation. Although the overall utilization has declined with the emergence of fluorodeoxyglucose–positron emission tomography/computed tomography (FDG-PET/CT), In-111 WBC scintigraphy maintains distinct advantages in specific clinical scenarios, such as in evaluating inflammatory bowel disease (IBD) and intra-abdominal infections. The minimal physiological bowel excretion of In-111 provides superior visualization of inflammatory foci within the abdomen compared to technetium-99m (Tc-99m) hexamethylpropyleneamine oxime (HMPAO) and FDG-PET. This characteristic makes In-111 particularly valuable for diagnosing active IBD, determining disease extent, and monitoring treatment response. Additionally, in cases of suspected intra-abdominal abscesses or postsurgical infections, the high specificity of In-111 WBC accumulation combined with minimal background interference often provides clearer diagnostic information than FDG-PET, where postsurgical changes and normal bowel uptake can confound interpretation.[3]
Although In-111 oxine has traditionally been used as a radiotracer for WBC labeling, Tc-99m HMPAO is also commonly used, each offering distinct advantages for specific clinical scenarios. Tc-99m HMPAO provides superior planar image quality, enables earlier imaging (0.5-4 hours postinjection), and reduces radiation exposure, making it particularly suitable for pediatric imaging. However, its 6-hour half-life can limit delayed imaging needed for indolent processes, and its normal activity in the gastrointestinal tract, urinary tract, and gallbladder may interfere with interpretation. Despite producing lower-quality planar and SPECT images, In-111 oxine offers distinct advantages, including higher labeling efficiency and minimal intestinal excretion, making it the preferred choice for abdominal infections and IBD. This is also compatible with concurrent Tc-99m nanocolloid bone marrow imaging due to different energy windows. Additionally, In-111's longer half-life (67 hours) allows for delayed imaging in chronic conditions. However, this benefit comes at the cost of higher radiation exposure to labeled cells, critical organs (particularly the spleen), and the whole body.[2]
FDG-PET has shown higher sensitivity than In-111 WBC scintigraphy in evaluating FUO.[4][5] For prosthetic joint infections, FDG-PET has demonstrated excellent diagnostic accuracy, with sensitivity and specificity of 95% and 93%, respectively, outperforming the combination of Tc-99m bone scan and In-111 WBC scintigraphy (sensitivity of 50% and specificity of 95%). Although the high costs and occasional lack of insurance reimbursement for non-cancer indications have limited the widespread adoption of FDG-PET, it may eventually replace other nuclear imaging modalities in many clinical scenarios. For example, despite cost limitations, FDG-PET/CT has shown promise in assessing COVID-19, particularly for evaluating disease severity and monitoring treatment response.[6] Nevertheless, in specific applications such as IBD and intra-abdominal infections, where physiological FDG uptake can complicate interpretation, In-111 WBC scintigraphy remains the preferred molecular imaging modality.[4] In spine infections, where In-111 WBC scans exhibit characteristically low sensitivity and problematic photopenic defects, FDG-PET/CT is the preferred molecular imaging modality. Appropriate use criteria have been established to guide the selection of nuclear medicine procedures for musculoskeletal infection imaging, promoting their effective and judicious application.[7]
Specimen Collection
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Specimen Collection
The preparation of In-111–labeled leukocytes for diagnostic imaging requires strict adherence to aseptic techniques and established protocols. The following provides an overview of the procedure based on established guidelines.[3][8] However, clinicians should always consult the latest recommendations when preparing imaging protocols. The process begins with collecting 40 to 80 mL of blood from adult patients (10–15 mL for pediatric patients) using at least a 20G needle to minimize cell damage.[8] Blood is drawn into a sterile container containing acid-citrate-dextrose (ACD) formulation A per European Pharmacopoeia) or heparin as an anticoagulant. Leukopenia is a relative contraindication due to reduced WBC labeling efficiency.
High-molecular-weight hydroxyethyl starch (HES) 200/0.5 or 200/0.6 (10% solution) is added to the blood-ACD mixture in a 1:10 ratio for cell separation. After 30 to 45 minutes of erythrocyte sedimentation, the leukocyte-rich plasma is collected and centrifuged at 150g for 5 minutes to separate the cells. The platelet-rich supernatant is then removed, and the leukocyte pellet is gently resuspended in cell-free plasma (CFP).
For leukocyte labeling, approximately 20 MBq (0.5 mCi) of In-111 oxine solution is added to the leukocyte suspension and incubated at room temperature for 10 minutes. After incubation, the cells are washed with PBS and resuspended in CFP, achieving a labeling efficiency of 50% to 80%. After visual inspection for clumps, clots, fibrin, and platelet aggregates, a 22-gauge (22G) or larger needle is used for injection to prevent cell damage. The typical adult dose ranges from 10 to 18.5 MBq (0.25–0.5 mCi). For pediatric patients, the recommended dose is 0.15 to 0.25 MBq/kg (0.004–0.007 mCi/kg), with a minimum administered activity of 1.85 to 2.3 MBq (50–75 μCi) and a maximum of 18.5 MBq (500 μCi).[2]
A strict aseptic technique must be maintained throughout the procedure, which should be conducted in a laminar flow hood or isolator with proper personal protective equipment (sterile gloves, mask, and cap). Accurate patient identification, labeling, and quality control procedures are essential. Dextrose in water solutions must be avoided, as it can cause clumping of labeled cells. This methodology minimizes cell damage while maximizing labeling efficiency for accurate diagnostic imaging.
Procedures
In most cases, no special patient preparation is required for the test. The labeled WBCs should be reinjected as soon as possible, but no later than 1 hour after the labeling procedure, as WBCs stored for longer than 3 hours experience a significant loss of cell viability.[3] The injection should be administered slowly using a 22G (0.7 mm diameter) needle or larger to prevent cell damage from shear stress.
Images are typically acquired at varying times based on the clinical situation, usually 1 to 4 hours or 16 to 30 hours after injection. Imaging times for planar images are typically 10 to 15 minutes per view, although longer times of 15 to 20 minutes may be necessary for areas with low count rates, such as distal limbs. Patients must be able to cooperate for whole-body or regional imaging, which may take 30 to 60 minutes to complete. Images obtained 16 to 24 hours postinjection may not provide significant additional information unless there is excessive residual blood pool activity in the early scans.
Early, temporary lung uptake is expected but should show almost complete clearance within 30 minutes postinjection.[2] Persistent focal or diffuse lung activity is abnormal and may indicate cell clumping or damage from the labeling procedure. Spleen activity should typically be higher than liver activity at all time points; if liver activity is equal to or greater than spleen activity, it may suggest cell damage, potentially making the scan nondiagnostic.[8]
Indications
In-111 WBC scintigraphy is a valuable diagnostic tool for detecting infections and inflammation, particularly when anatomical imaging modalities are inconclusive or when functional imaging is needed to localize subtle inflammatory processes. The primary applications include evaluating appendicular osteomyelitis, prosthetic joint infections, vascular graft infections, intra-abdominal infections, infected devices, and diabetic foot ulcers. Additionally, this technique can aid in detecting and localizing occult infection sites and assessing disease extent in various clinical scenarios, as mentioned below.
- Inflammatory bowel disease: In-111 WBC scintigraphy can aid in evaluating the extent and activity of inflammation in IBD, particularly when clinical findings or conventional imaging, such as CT, are inconclusive.
- Intra-abdominal infections: WBC scintigraphy is effective for identifying intra-abdominal abscesses, postoperative infections, and bowel-related infections. In-111 WBC scintigraphy is particularly advantageous for abdominal imaging due to the reduced bowel excretion of In-111–labeled leukocytes, compared to Tc-99m HMPAO-labeled WBCs.
- Osteomyelitis of the appendicular skeleton: In-111 WBC imaging is effective for diagnosing osteomyelitis in the appendicular skeleton, including the long bones and pelvis. However, FDG-PET/CT or gallium-67 citrate is preferred for suspected spinal osteomyelitis due to its superior sensitivity and specificity.[7] Gallium-67 scintigraphy is preferred over In-111 WBC for spinal infections because it detects both neutrophilic and granulomatous inflammation. However, FDG-PET/CT has largely replaced both modalities due to its superior sensitivity, resolution, and ability to provide earlier and more accurate detection.
- Diabetic foot infections: In-111 WBC scintigraphy aids in differentiating soft tissue infections from underlying osteomyelitis in diabetic foot ulcers. This is particularly important for patients with nonhealing ulcers or chronic wounds, where timely and accurate diagnosis is essential for guiding management and improving outcomes.
- Infected joint prostheses and vascular grafts: In-111 WBC scintigraphy is useful for detecting infections in prosthetic joints and vascular grafts. When imaging prosthetic joints, combining In-111 WBC scintigraphy with bone marrow imaging (eg, Tc-99m sulfur colloid scintigraphy) enhances diagnostic accuracy by assessing whether the bone marrow is actively involved in the inflammatory process. This helps differentiate infection from aseptic loosening. Discordant uptake by the radiotracers is indicative of prosthetic joint infection.
- Fever of unknown origin: In-111 WBC scintigraphy is a valuable diagnostic tool for evaluating FUO in patients with a high clinical suspicion of infection, especially when the source of infection cannot be identified using conventional diagnostic approaches.[4]
- Postoperative abscesses: In-111 WBC scintigraphy is highly sensitive for detecting localized infections or abscesses after surgery, particularly when clinical findings and conventional imaging, such as CT, are inconclusive.
- Infections associated with medical devices: In-111 WBC scintigraphy is useful for detecting infections related to indwelling medical devices, such as central venous catheters, pacemakers, defibrillators, and other implantable devices.
Miscellaneous Applications
In-111 WBC scintigraphy can detect inflammatory or infectious processes in the lungs and central nervous system. However, its use for these indications is limited due to the availability of alternative modalities, such as CT or magnetic resonance imaging (MRI), which are more commonly employed. While echocardiography remains the primary diagnostic tool for endocarditis, In-111 WBC scintigraphy may occasionally aid in identifying complications, such as perivalvular abscesses, septic emboli, or infections involving prosthetic heart valves.
Advantages and Limitations
In-111 WBC scintigraphy offers distinct advantages in specific clinical settings, particularly in areas such as the abdomen, where the bowel excretion of Tc-99m HMPAO-labeled WBCs may interfere with interpretation.[3] Moreover, combining In-111 WBC scintigraphy with bone marrow imaging using Tc-99m sulfur colloid has enhanced diagnostic accuracy in prosthetic joint infections by distinguishing infectious etiologies from aseptic processes. However, there are notable limitations. In-111 WBC scintigraphy offers lower spatial resolution compared to Tc-99m HMPAO-labeled WBC scintigraphy, resulting in suboptimal planar and single-photon emission computed tomography (SPECT) image quality.
Additionally, In-111 has a longer half-life (67 hours), leading to higher radiation exposure to labeled leukocytes, critical organs (eg, spleen), and the whole body. While generally more expensive than Tc-99m HMPAO-labeled WBC scans, In-111 offers advantages in specific situations, especially abdominal imaging, where its reduced bowel excretion makes it more reliable. These advantages can justify the increased cost in appropriate clinical scenarios. The shift toward FDG-PET/CT is supported by reviews showing its superior sensitivity in many FUO cases.[5] Despite these drawbacks, In-111 WBC scintigraphy remains a unique and valuable imaging modality in certain clinical scenarios, particularly in chronic or complex infections where the advantages of physiological imaging outweigh concerns about radiation exposure.
Potential Diagnosis
In-111 WBC scans can identify various infections and inflammatory conditions but have significant limitations and should not be used as standalone diagnostic tools.[4] For optimal results, obtaining a thorough clinical history and fostering effective communication across the multidisciplinary healthcare team are essential to maximize patient outcomes.[9]
Normal and Critical Findings
Interpreting an In-111 WBC scan requires a detailed understanding of normal biodistribution patterns, physiological variants, and pathological findings.
Normal Findings
At 18 to 24 hours postinjection, the normal biodistribution of In-111–labeled leukocytes includes uptake in the spleen, liver, and bone marrow, with no uptake in the bowel or bladder. These organs are part of the reticuloendothelial system, responsible for the sequestration and recycling of labeled leukocytes. Typically, the spleen exhibits the highest uptake, followed by the liver and bone marrow.[8] Transient pulmonary activity observed up to 4 hours postinjection is considered normal, as it reflects temporary sequestration of radiolabeled leukocytes in the pulmonary vasculature. Persistent pulmonary activity beyond 4 hours may indicate pathological processes, such as infection or inflammation in the lungs.
Abnormal Findings
Pathological uptake is typically characterized by focal or diffuse areas of increased radiotracer accumulation outside the normal biodistribution. These areas correspond to sites of active infection or inflammation.
Abscess Detection
The uptake of In-111–labeled leukocytes in an abscess is typically equal to or greater than that in the liver. About 50% of abscesses can be detected as early as 4 hours postinjection, with diagnostic sensitivity exceeding 90% by 24 hours. This delayed uptake reflects the accumulation of activated leukocytes at the infection site.
Osteomyelitis
In cases of osteomyelitis, radiolabeled leukocyte uptake is significantly increased in the infected bone, reflecting the recruitment of leukocytes to the site of inflammation. However, a false-negative result may occur if the patient has received intravenous antibiotics before the scan, as these treatments can suppress the inflammatory response, reducing leukocyte migration to the infected site.
Infected Orthopedic Hardware
In-111 WBC scans can detect infections associated with orthopedic hardware or prostheses, but the interpretation can be challenging due to the displacement of the bone marrow caused by the hardware. This displacement alters the expected biodistribution of radiolabeled leukocytes in the affected area. To improve diagnostic accuracy, comparison with a Tc-99m sulfur colloid scan is often necessary. Discordant findings between the In-111 WBC scan (showing increased uptake) and the Tc-99m sulfur colloid scan (showing reduced uptake due to bone marrow suppression or displacement) suggest an acute infection. SPECT or hybrid SPECT/CT imaging can further aid in precise localization and differentiation between infection and noninfectious causes.
Key Considerations
Persistent or atypical patterns of In-111 uptake outside the normal biodistribution, particularly in the lungs, gastrointestinal tract, or soft tissues, warrant further investigation. Variability in findings may be influenced by technical factors, the patient's immune status, or recent treatments such as antibiotics or corticosteroids. These factors must always be considered during interpretation.
Interfering Factors
False positives in In-111 leukocyte scintigraphy are primarily caused by noninfectious inflammatory conditions, which often demonstrate increased uptake of labeled leukocytes, leading to a false-positive result. Other misleading patterns can occur with conditions such as IBD, accessory spleens, acute hemorrhage, hematomas, neoplasms, and foreign body reactions.[8]
False-negative results also present significant challenges. Chronic infections, particularly indolent abscesses, often fail to demonstrate the expected accumulation of labeled leukocytes. Lymphocyte-mediated infections, such as tuberculosis and sarcoidosis, typically exhibit normal or reduced uptake. Hepatic and splenic abscesses present unique difficulties because these organs metabolize In-111 as part of their normal function, which can mask localized infection. Additionally, prior antibiotic therapy may reduce scan sensitivity, although this effect varies depending on the treatment duration and infection type.
Unlike Tc-99m HMPAO, In-111 demonstrates minimal physiological bowel uptake, providing an advantage in abdominal imaging. However, vertebral infections often result in false-negative findings. Bone marrow conditions, particularly hemoglobinopathies, can produce uptake patterns that resemble infection, though careful comparison with bone marrow imaging can help distinguish these findings. As with all molecular imaging, accurate interpretation requires close clinical correlation, integration of the patient’s clinical history, and comparison with previous imaging results.
Complications
A potential complication of In-111–labeled WBC scans is radiation exposure, which primarily affects the spleen, liver, and bone marrow.[8] The effective radiation dose for In-111 WBC scans in adults ranges from 6 to 12 mSv, while pediatric patients may receive a higher dose per kilogram, typically ranging from 10 to 20 mSv. In contrast, Tc-99m HMPAO-labeled WBC scans deliver a significantly lower effective dose, typically 0.7 to 1.0 mSv, making Tc-99m HMPAO the preferred radiopharmaceutical for pediatric patients due to their greater radiosensitivity. The decision to use In-111 WBC scans should be made cautiously, with clinicians discussing the risks, benefits, and alternatives with patients or their families.[8]
Patient Safety and Education
Before conducting a radiolabeled nuclear scan with indium, it is essential to discuss with patients the clinical utility, radiation exposure, and overall process of the In-111 WBC scan.
Clinical Significance
In-111–labeled WBC scintigraphy provides valuable diagnostic information for detecting and localizing infection and inflammation, mainly when conventional imaging modalities such as CT or MRI are inconclusive. This technique offers high specificity by directly visualizing leukocyte migration to active infection sites, enabling differentiation from noninfectious inflammatory processes in many cases.
Studies have reported sensitivities ranging from 74% to 92% and specificities from 68% to 92% for osteomyelitis and prosthetic joint infections.[1] Diagnostic accuracy improves when combined with bone marrow scintigraphy using Tc-99m sulfur colloid and can be enhanced with delayed imaging. This dual-tracer approach is particularly beneficial in differentiating true infections from aseptic prosthetic loosening, which can present similar clinical and imaging findings.
In-111 WBC scintigraphy is useful for detecting intra-abdominal infections and IBD due to its minimal physiological bowel excretion, unlike Tc-99m HMPAO-labeled leukocytes, which exhibit significant gastrointestinal activity. This advantage allows for better detection of intra-abdominal abscesses and active inflammatory sites in IBD, especially when endoscopy or cross-sectional imaging fails to provide definitive localization.
Despite the increasing role of FDG-PET/CT in infectious disease imaging, In-111 WBC scintigraphy remains clinically significant in evaluating vascular graft infections, infected central venous catheters, and diabetic foot infections. The high specificity of In-111 WBC scintigraphy aids in distinguishing actual infections from postoperative changes, sterile inflammation, or other conditions with similar presentations. However, its sensitivity is lower in chronic infections, particularly in spinal conditions like vertebral osteomyelitis, where In-111 WBC imaging may yield false-negative results due to limited leukocyte infiltration. In these cases, FDG-PET/CT is often preferred for its superior sensitivity.
When interpreting In-111 WBC scintigraphy results, it is crucial to consider the clinical context and pre-test probability of infection, as diagnostic performance can vary based on the indication.[1] The PPV and NPV are highly dependent on disease prevalence and should not be generalized across all infectious conditions. Correlating multimodal imaging by integrating nuclear scintigraphy findings with anatomical imaging and laboratory data is essential for achieving optimal diagnostic accuracy.
Although In-111 WBC scintigraphy remains relevant in specific clinical scenarios, newer imaging modalities, particularly FDG-PET/CT, are gaining preference for some infections due to their higher sensitivity, better spatial resolution, and ability to assess metabolic activity. However, In-111 WBC scintigraphy retains distinct advantages in specific applications, such as intra-abdominal infections, IBD, and prosthetic joint infections, where its unique biodistribution properties and compatibility with dual-tracer bone marrow scintigraphy enhance diagnostic performance.[3]
References
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