European Journal of Nuclear Medicine and Molecular Imaging

, Volume 30, Issue 12, pp 1665–1673

The value of SPET/CT in chronic osteomyelitis

Authors

    • Department of Diagnostic RadiologyEberhard-Karls Universität
  • Susanne Martina Eschmann
    • Department of Nuclear MedicineEberhard-Karls-Universität
  • Christina Pfannenberg
    • Department of Diagnostic RadiologyEberhard-Karls Universität
  • Dieter Storek
    • Department of Traumatology and Orthopaedic SurgeryEberhard-Karls-Universität
  • Florian Dammann
    • Department of Diagnostic RadiologyEberhard-Karls Universität
  • Reinhard Vonthein
    • Department of Medical BiometryEberhard-Karls-Universität
  • Claus D. Claussen
    • Department of Diagnostic RadiologyEberhard-Karls Universität
  • Roland Bares
    • Department of Nuclear MedicineEberhard-Karls-Universität
Original Article

DOI: 10.1007/s00259-003-1321-z

Cite this article as:
Horger, M., Eschmann, S.M., Pfannenberg, C. et al. Eur J Nucl Med Mol Imaging (2003) 30: 1665. doi:10.1007/s00259-003-1321-z

Abstract

Immunoscintigraphy with technetium-99m labelled anti-granulocyte antibodies (AGA) is an equivalent technique to imaging with in vitro-labelled leucocytes, which is now considered state of the art in the diagnostic work-up of patients with suspected post-traumatic chronic osteomyelitis. In this study, we evaluated the use of a combined single-photon emission tomography/computed tomography (SPET/CT) device to improve detection and anatomical definition of inflammatory bone lesions. Twenty-seven patients with 29 sites of suspected bone infection underwent immunoscintigraphy with 750 MBq 99mTc-labelled AGA. Planar scans were acquired immediately, 4 h and 24 h after injection, and combined SPET/CT was performed using a dual-head multifunctional gamma camera equipped with a low-power X-ray system. Accumulation of AGA in inflammatory lesions was quantitated, comparing uptake at 4 and 24 h after injection. The validation was based on culture data derived from surgical or biopsy samples (20 lesions in 18 patients) or clinical follow-up without further therapy for more than 6 months (nine lesions). On a lesion-by-lesion basis 19 true positive, one false positive and nine true negative findings were obtained. SPET/CT correctly identified the location of all positive foci in the appendicular skeleton and that of a cold lesion in the axial skeleton. It also enabled differentiation between soft tissue infection, septic arthritis and osteomyelitis, as well as between cortical, corticomedullary and subperiosteal foci. Sensitivity was identical for SPET and SPET/CT (100%), whereas specificity was improved from 78% to 89% by the use of SPET/CT. Combined SPET/CT improves the accuracy of immunoscintigraphy by allowing correct differentiation between soft tissue infection and bone involvement. This technique may gain clinical relevance in the selection of patients for surgical therapy.

Keywords

Chronic post-traumatic osteomyelitisSPET/CTImmunoscintigraphyAnti-granulocyte antibodiesSurgical planning

Introduction

Immunoscintigraphy (IS) with technetium-99m labelled monoclonal anti-granulocyte antibodies is known to be highly sensitive and specific in diagnosing infectious disease [1, 2, 3]. Scan analysis, however, is often difficult. While the presence of inflammation can be substantiated or ruled out by quantitative image analysis, exact anatomical definition of infectious foci is very demanding, in particular if they are located in distant parts of the extremities. The combined use of SPET and image fusion might solve this problem. Recently a new type of imaging device has been introduced that permits both functional and anatomical images to be obtained: combined single-photon emission tomography/computed tomography (SPET/CT). By combining a dual-head gamma camera with a low-power X-ray system, sequential acquisition of SPET and CT data has become possible, allowing for perfect overlay and precise correlation of the two data sets. First clinical experiences indicate that accuracy of scan interpretation can be improved by direct correlation of functional and morphological abnormalities [4, 5]. Use of this new technique in conjunction with a highly specific agent for detection of inflammatory disease might create a new and powerful approach to diagnose infectious foci. The aim of this study was to evaluate the utility of SPET/CT as an adjunct to immunoscintigraphy with 99mTc-labelled monoclonal anti-granulocyte antibodies in a group of patients with bone abnormalities suspected of having relapsing post-traumatic osteomyelitis.

Materials and methods

Patients

Between February and November 2002, a total of 27 patients (22 males and 5 females; age range 20–90 years, mean 48 years) with a history of trauma and secondary bone infection were studied prospectively. In all of them, reactivation of chronic post-traumatic osteomyelitis was suspected because of clinical signs of inflammation such as swelling, heat, erythema, pain, fever or fistulae, and/or typical laboratory parameters (increased ESR, CRP, WBC). The study was approved by the institutional ethics committee, and all patients gave their written informed consent prior to inclusion.

Immunoscintigraphy

A commercially available kit (Scintimmun Granulozyt; Schering AG, Berlin, Germany) containing 1 mg murine monoclonal antibody against NCA-95 was used in the study. The labelling procedure was performed according to the manufacturer's instructions. Patients received typically 0.5 mg antibody labelled with 750 MBq 99mTc by slow intravenous injection. Immediately thereafter, blood pool scans of the suspected areas of inflammation (acquisition time 2 min) as well as whole-body scans (acquisition speed 40 cm/min) were obtained using a double-head large field of view gamma camera (BodyScan; Siemens, Erlangen, Germany) equipped with high-resolution low-energy collimators. Imaging was repeated at 3–4 h p.i. with adapted acquisition protocols (planar images: 106 counts/view; whole-body scans: 5 cm/min). Twenty-four hours p.i., static scans of suspected areas of inflammation (5×105 counts/view) were again acquired.

Combined SPET/CT

Combined SPET/CT was performed subsequently with a dual-head multifunctional gamma camera equipped with a low-power X-ray system (Millennium VG & Hawkeye; GE Medical Systems, Milwaukee, WI). Transmission data were obtained by "half-scan" acquisition over 220° in 16 s for each transaxial slice (full field of view: 40 slices/10 min.). The protocol for emission computed tomography (ECT) was as follows: 360° acquisition, high-resolution low-energy collimators, matrix size 128×128, 3° steps, 40 s/frame. Matching pairs of transmission and emission images were fused by overlaying the CT and SPET data using a dedicated nuclear medicine software package (eNTEGRA; GE Medical Systems, Milwaukee, WI).

Image analysis

In the first phase of image analysis, scintigraphy (planar as well as SPET) and transmission images were independently evaluated by two experienced nuclear medicine physicians (S.M.E., R.B.) or radiologists (M.H., C.P.) who were blinded with regard to previous imaging results [X-ray, magnetic resonance imaging (MRI), high-end CT]. The readers were asked to describe any abnormal foci with regard to location (intra- or extraosseous), extension and origin (inflammatory vs unspecific). Subsequently all images were re-interpreted by nuclear medicine specialists or radiologists by consensus. Finally, the fused transmission and emission images were read by both teams together. Antibody uptake was graded as absent, mild or marked. A quantitative analysis was performed by comparing antibody uptake at 4 and 24 h p.i., derived from manually drawn regions of interest. An uptake ratio of 1 over 24 h was considered highly suspicious, and a ratio of >1.1 was deemed specific for infection. Uptake ratios of <1 over 24 h were considered unspecific for infection because of lack of antibody accumulation. In addition, we evaluated the local extension of antibody uptake by using 50% isocontours of SPET images, defining the maximum as 100%. In patients with suspicion of spondylodiscitis, even initially "cold" lesions were considered positive for infection if the uptake ratio over time was >1 [6, 7].

Statistical analysis

Sensitivities and specificities with regard to correct detection of infectious foci were calculated for scintigraphy (planar and SPET) and SPET/CT and expressed as 95% confidence intervals (C.I.). The degree of inter-observer agreement was measured by kappa coefficient (κ). The utility of uptake ratios for the diagnosis of infectious disease was analysed by ROC analysis.

Validation

Final diagnoses were established by surgery and cultures in 20 sites of 18 patients. In nine patients who were not operated on, clinical course over a period of at least 6 months after cessation of any medical treatment was used to rule out active inflammation.

Results

Twenty-seven patients with a total of 29 sites of suspected post-traumatic osteomyelitis were studied. Final diagnoses and a direct comparison of the interpretation of immunoscintigraphy (planar + SPET) and SPET/CT are summarised in Table 1. Table 2 shows numerical results of both methods for different types of disease. In four patients, active bone infection requiring surgery with intramedullary curettage was confirmed. In one patient, cultures were negative, although surgery revealed a bone hole filled with cheese-like material considered to represent low-grade infection. Four patients had a soft tissue infection without bone involvement (one phlegmon and three fistulae). Another four patients had a soft tissue infection with "cortical reaction", without erosion. In one patient, multilevel spondylodiscitis was present. Five patients had joint empyema, and in one patient we found septic prosthetic loosening. Nine suspected sites turned out to be free of infection: Eight could be attributed to inflammatory reactions following surgery (n=6) or rheumatic arthritis (n=2). In one of them a false-positive result was obtained with both methods (uptake ratio =1.0). In one patient, SPET/CT correctly identified an accidental contamination of the skin. Using 50% isocontours and axial and coronal slices, SPET/CT provided exact delineation of infectious foci in all patients.
Table 1

Results of immunoscintigraphy (planar + SPET) and SPET/CT, according to the type of infection

Patient

Final diagnosis

Immunoscintigraphy

SPET/CT

Ratioa

1

Soft tissue infection

Soft tissue infection

Soft tissue infection

1.3

2

Infection of soft tissue + cortex + medulla

OM

OM + soft tissue infection + sequestra

1.3

3

Infection of soft tissue + cortex + medulla

Soft tissue infection

Infection of soft tissue + cortex + medulla

1.6

4

Septic prosthetic loosening

Septic prosthetic loosening

Septic prosthetic loosening

1.4

5

Infection of soft tissue + cortex

Soft tissue infection + OM

Infection of soft tissue + cortex

1.0

6

Infection of soft tissue + cortex

OM

Infection of soft tissue + cortex

1.0

7

Septic spondylodiscitis

Negative

Septic spondylodiscitis

1.0

8

Joint infection

Septic prosthetic loosening

Joint infection

1.5

9

Inflammation

Joint infection

Joint infection

1.0

10

Inflammation

Inflammation

Inflammation

0.8

11

Infection of soft tissue + cortex + medulla

OM

Infection of soft tissue + cortex + medulla

1.0

12

Infection of soft tissue + cortex + medulla

Soft tissue infection + OM

Infection of soft tissue + cortex + medulla

1.0

13

Soft tissue infection

Soft tissue infection

Soft tissue infection

1.0

14

Infection of soft tissue + cortex

OM

Infection of soft tissue + cortex

1.4

15

Soft tissue infection

Soft tissue infection

Soft tissue infection

1.0

16

Soft tissue infection

OM

Infection of soft tissue + cortex

1.5

17

Joint infection

Joint infection

Joint infection

1.0

18

Soft tissue infection

Soft tissue infection + OM

Soft tissue infection

1.5

19

Joint infection

Joint infection

Joint infection

1.5

20b

Joint infection

Joint infection

Joint infection

1.2

21b

No infection

Negative

Negative

0.8

22

Artefact

Soft tissue infection

Artefact

0.7

23

No infection

Negative

Negative

0.7

24

No infection

Negative

Negative

0.6

25

No infection

Negative

Negative

0.1

26b

Osteomyelitis

OM

OM

1.4

27b

No infection

Negative

Negative

0.2

28

No infection

Negative

Negative

0.2

29

Joint + soft tissue infection

Joint infection

Joint + soft tissue infection

1.2

OM, Osteomyelitis

aRatio of antibody uptake at suspected sites of infection (24/4 h p.i.)

bSame patient, two suspected sites of infection

Table 2

Results of immunoscintigraphy (planar + SPET) and SPET/CT related to type and location of infection

Infection type

No.

Immunoscintigraphy

SPET/CT

Correct

Incorrect

Correct

Incorrect

1. Soft tissue infectiona

8

3

5

8

0

2. Soft tissue infection + OM

4

3

1

4

0

3. Osteomyelitis

1

1

0

1

0

4. Joint infection

5

4

1

5

0

5. Septic prosthetic loosening

1

1

0

1

0

6. Spondylodiscitis

1

0

1

1

0

7. Acute inflammation

2

1

1

1

1

8. No infection (e.g. after surgery, trauma)

6

6

0

6

0

9. Artefact (e.g. skin contamination)

1

0

1

0

0

Total

29

17

12

28

1

OM, Osteomyelitis

aIncluding cases with soft tissue infection and reactive cortical uptake

Figure 1 shows the findings in a 24-year-old male patient complaining of progressive crural pain and limping, 4 years after open tibial fracture and multiple surgical interventions. Planar scintigraphy and SPET revealed focal tracer uptake indicative for relapsing chronic osteomyelitis. Combined SPET/CT demonstrated the extent of infection, correctly localising infection at the cortical bone with no activity shown in the marrow or neighbouring soft tissue. In another patient with osteomyelitis, SPET/CT additionally detected accompanying soft tissue infection following cortical perforation after pinning (Fig. 2).
Fig. 1

Anti-granulocyte immunoscintigraphy in a 24-year-old male patient with a history of open femoral fracture and multiple operations until 4 years previously. The planar scan and SPET reveal focal tracer uptake suggestive for recurrent chronic osteomyelitis (not shown). SPET/CT correctly demonstrates the extent of infection in cortical bone areas without involvement of the bone marrow (arrows). Note also precise lesion delineation, after applying 50% isocontours

Fig. 2

Anti-granulocyte scintigraphy (planar and SPET) and SPET/CT in a 40-year-old male patient with a history of a traumatic fracture of the right tibia and external fixation 5 years previously. At the time of SPET/CT, he presented local swelling, erythema, pain and fistula formation. SPET/CT accurately reveals the extent of infection within bone marrow along a pinhole through the anterior cortex (arrows)

Soft tissue infection without bone involvement was hard to classify by scintigraphy alone. In two out of five cases, planar scintigraphy and SPET falsely diagnosed additional osteomyelitis, which could be correctly excluded by SPET/CT, as confirmed by surgery. In three patients with soft tissue infection and "reactive cortical" uptake, differentiation from osteomyelitis with soft tissue infection was difficult, resulting in three false positive results with planar scintigraphy and SPET. In the group of five patients interpreted as having bone infection by planar scintigraphy and SPET, combined SPET/CT revealed additional soft tissue infection in two cases. Two other patients of this group had soft tissue infection without bone involvement, correctly diagnosed by SPET/CT and then confirmed by surgery. In one of two cases interpreted as septic prosthetic loosening by planar scintigraphy and SPET, combined SPET/CT and surgery (arthroscopy) revealed joint empyema. The remaining five patients with joint infection were correctly diagnosed by planar scintigraphy and SPET as well as by SPET/CT. The second case of septic prosthetic loosening was also diagnosed correctly by both methods.

In a patient with acute spondylodiscitis, scintigraphy was first considered false negative. Multilevel, bilateral photopenic areas on the static scan of the lumbar spine, obtained 4 h p.i., were attributed to scoliosis. However, quantitative analysis of antibody uptake revealed areas of focal increase over 24 h (uptake ratio >1.0), indicating infection. SPET/CT finally enabled the correct diagnosis by demonstrating disc and vertebral body destruction due to spondylodiscitis. Anti-granulocyte immunoscintigraphy was true negative for infection in seven patients. A false positive finding was obtained in only one patient suffering from rheumatoid arthritis, which caused focal antibody accumulation (uptake ratio =1) in a small joint of the first toe.

The overall results of immunoscintigraphy vs SPET/CT are shown in Tables 3 and 4. Sensitivity was 100% for both while specificity was 78% for immunoscintigraphy and 89% for SPET/CT. Analysis of inter-observer agreement with regard to localisation of infectious foci resulted in κ=0.68 for immunoscintigraphy and κ=1.0 for SPET/CT, demonstrating the high reliability of the new method. Interpretation of immunoscintigraphy was changed on the basis of SPET/CT in eight patients (27.5%): In a patient suspected of having septic prosthetic loosening, joint empyema could be corrected diagnosed by SPET/CT (Fig. 3). In another patient, SPET/CT enabled the diagnosis of spondylodiscitis, as mentioned above. In two patients with suspected soft tissue and bone infection, SPET/CT was able to exclude osteomyelitis. In a further patient, SPET/CT identified skin contamination as the cause of persisting antibody uptake, thus ruling out soft tissue infection. Finally in three patients, soft tissue infection with reactive cortical tracer accumulation, but without accompanying osteomyelitis, could be diagnosed on the basis of SPET/CT, avoiding unnecessary bone surgery.
Table 3

Contingency table of immunoscintigraphy diagnosis by final diagnosis

Correct

Incorrect

Total

Infection

  No.

20

0

20

  %

100.00

0.00

No infection

  No.

7

2

9

  %

77.78

22.22

Total

27

2

29

Table 4

Contingency table of SPET/CT diagnosis by final diagnosis

Correct

Incorrect

Total

Infection

  No.

20

0

20

  %

100.00

0.00

No infection

  No.

8

1

9

  %

88.89

11.11

Total

28

1

29

Fig. 3a–c

Anti-granulocyte immunoscintigraphy in a 65-year-old patient, 11 months after implantation of a knee prosthesis. At the time of scintigraphy, the patient complained of pain and local swelling, especially during exercise. The laboratory data are highly suspicious for infection. a Planar scintigraphy and b SPET show linear uptake on both sides of the joint, mimicking the contours of the prosthesis (arrows). c Combined SPET/CT demonstrates tracer accumulation outside of bone, in the swollen soft tissue and in the synovium of the knee joint owing to empyema (arrows)

By applying 50% isocontours to SPET images, the main location of infection could be correctly depicted in all patients (an example is shown in Fig. 4). Transmission scans did not reveal cortical bone erosion or destruction outside these areas.
Fig. 4a–c

Anti-granulocyte immunoscintigraphy in a 54-year-old patient with a soft tissue infection of the big toe after trauma. a SPET images show tracer uptake in the distal phalanx of the right hallux (arrows). b SPET/CT demonstrates uptake mainly in the soft tissue, with only reactive tracer accumulation in the bone cortex and no erosion (arrow). c 50% isocontours allow better depiction of the extent of infection (arrow)

Quantitative analysis of antibody uptake revealed optimal discrimination between infection and non-infectious foci was achieved by using 1.0 as the cut-off (Fig. 5). All patients with proven infection, either soft tissue, joint space or bone, had an uptake ratio of ≥1 (Table 1). A borderline ratio of 1.0 was registered in eight patients. In seven of them infection was confirmed at surgery. One patient suffered from severe inflammation due to rheumatoid arthritis. Uptake ratios of non-infectious lesions were in the range 0.2–0.8.
Fig. 5

ROC analysis on the use of antibody uptake ratios (24/4 h p.i.) to classify focal lesions in anti-granulocyte immunoscintigraphy (infection vs non-infection). Optimal discrimination was achieved using a ratio of 1.0 as the cut-off

Discussion

Even today, diagnosis of chronic post-traumatic osteomyelitis presents a challenge for all imaging modalities. Skeletal injuries after traffic, sport or industrial accidents may cause heavily distorted bone morphology even when treated by modern orthopaedic surgery. As a consequence, recognition of post-traumatic or post-surgical bone infection is often very difficult. In most cases, clinical or biochemical parameters alone are not sufficient to establish a correct diagnosis. Therefore imaging modalities which are both sensitive and specific for infection are needed to plan further patient management. Nuclear medicine plays an important role in the diagnosis of musculoskeletal infections. Leucocyte scanning is still considered the gold standard in the diagnosis of chronic post-traumatic or postoperative osteomyelitis. A more recent approach, immunoscintigraphy with 99mTc-labelled antigranulocyte antibodies, has overcome the main impediment of leucocyte scanning, namely the difficult in vitro handling of human blood cells.

Quantitative analysis of antibody uptake in suspected foci of infection over time proved to be helpful in confirming or ruling out infection (vs unspecific hyperaemia). By using an uptake ratio of ≥1 as cut-off, all foci of infection could be correctly identified in our study. This was also true for the axial skeleton, which is often hard to interpret owing to the presence of antibody uptake in the haematopoietic bone marrow [8]. Thus, a higher sensitivity (100%) and specificity (89%) could be achieved in comparison to other studies on this issue. A sensitivity of 100%/77% and a specificity of only 60%/50% was calculated for MRI/immunoscintigraphy + bone scintigraphy in a similar study in patients with chronic osteomyelitis [9].

A common disadvantage of all scintigraphic techniques in localising infection is poor image resolution, frequently combined with the lack of anatomical landmarks. However, exact localisation of infectious foci is of paramount interest if surgical treatment is considered. Therefore, supplementary anatomical data from planar X-ray films or CT are desirable. CT is particularly helpful in detecting small areas of cortical destruction, foci of gas, foreign bodies, sequestration, involucra or cloacae [10, 11, 12]. In addition, CT can detect surrounding soft tissue abscesses, the replacement of the normal bone marrow by pus, and joint empyema. Visual fusion of CT with scintigraphy often proves difficult, in particular in patients with severely distorted bone structure. SPET/CT combines the known advantages of anti-granulocyte immunoscintigraphy [13, 14, 15] with anatomical imaging by low-dose CT. The high inter-observer agreement found in our study demonstrates the great reliability of this new method.

As a consequence, fused images may guide the surgeon to the most suitable place to operate, e.g. windowing the diaphyseal cortex and avoiding vital structures. Furthermore, they may help in adapting the width of the window and the extent of debridement of the inner bone surface, which in turn may reduce postoperative instability. Recognition of sequestra or involucra in patients with post-traumatic osteomyelitis is often difficult, leading to unnecessary operations such as opening the intramedullary canal in patients with soft tissue infection without bone involvement [16]. Our results indicate that anti-granulocyte immunoscintigraphy with SPET/CT allows accurate localisation of infectious foci, and in particular differentiation between soft tissue infections and osteomyelitis of the appendicular skeleton. Since therapeutic management differs for these two situations, SPET/CT may gain high clinical relevance in patients who are considered for surgical treatment of post-traumatic chronic osteomyelitis.

In summary, we recommend SPET/CT as a superior method for the diagnosis of chronic post-traumatic osteomyelitis and/or accompanying joint and soft tissue infection compared to SPET, enabling better localisation of infection foci and optimised surgery planning in a one-step procedure.

Copyright information

© Springer-Verlag 2003