Technetium-9 9m-Labeled Anti-Granulocyte Antibodies in Suspected Bone Infections

Andreas L. Hotze, Bernd Briele, Bettina Overbeck, Joachim Kropp, Frank Gruenwald, Mohammed A. Mekkawy, Alexander von Smekal, Frank Moeller, and Hans J. Biersack

Departments ofNuclear Medicine and Orthopedics, University ofBonn, Germany and Department ofRadiotherapy and Nuclear Medicine, Assiut University Hospital, Assiut, Egypt

The procedure for labeling white blood cells (leukocytes, The introductionof @“Tc-labeIedanti-granulocyteantibodies granulocytes) with radioactive tracers has changed signifi seemed to provide advantages in comparison with formerly cantly over the last few years. The separation and radio used in vitro methodsto label autologouswhite bloodcells labeling of mixed leukocytes with ‘‘‘In-oxinewas first for inflammationimaging. For this reason, we have undertaken introduced into clinical medicine by Thakur et al. (12) in a studyto evaluatethedinicaJsignificanceofthismethod. 1976. This approach is still considered the “goldstandard― Thirty unselectedpatients with suspected bone infections for the detection ofseptic inflammation lesions. A method werestudiedprospectivelyusingthemonoclonal@‘Tc-lato label blood cells with 99mTc@HMPAObecame available beled anti-granulocyte antibody. Twenty patients were re in 1986 (13), and since 1987/88 a monoclonal murine ferred with suspected infections of the peripheral bones antibody against human granulocytes has been available (GroupI), as well as 10 patientswith suspectedinfectionsof thespine(GroupII).Planarwhole-bodyscanswere performed for clinical trials (14,15). 4 hr and 20 to 24 hr after administrationof 500 MBqof the Labeling with both ‘‘‘In-oxineand 99mTc..HMpAO has labeled antibody. Scans were considered positive for a bac some disadvantages, including the relatively time-consum terial (septic) infectionwhen a focally increased antibody ing separation procedure and the unfavorable physical accumulation occurred. All scans were evaluated in blinded properties of ‘‘‘Infor gamma camera imaging. The intro fashionby two experiencedreaders.Of the 20 studiesfrom duction of 99mTclabeled monoclonal anti-granulocyte an GroupI patients,fourfalse-positivescintigraphicfindingswere tibodies (AGAB) thus seemed to be an advantage over the observed,andonefalse-negative,resultingin a specificityof former modalities which involve cell separation. only 64% and a sensitivityof 89%. In GroupII (10 studies), The aim of this study was to evaluate whether the use fivescansweretrue-negative,andfivefalse-negative.For of these AGABs would also provide more precise infor both groups, the specificity of the scintigraphic method was mation on questionable bone infections. Furthermore, we quite low (75%), and the sensitivitywas also relativelylow (57%). The results of this study demonstrate that in an were interested in evaluating the sensitivity and accuracy unselected patient population in whom the diagnosis is not ofinflammation imaging using this antibody. We therefore known,scintigraphywith @“Tc-anti-granuIocyteantibodiesis initiated a clinical study in orthopedic patients with equiv not a reliable method for detecting septic inflammatory le ocal bone infections including both peripheral bones and sions.In addition,use of this methodexcludessepticlesions the spine. with only a moderate likelihood (83% negative predictive value). J NucI Med 1992; 33:526—531 MATERIALS AND METHODS The AGABused for this studywasproducedand suppliedby Behringwerke AG (Frankfurt, Germany). The AGAB is an im munoglobulin of the IgG isotype with a molecular weight of he current diagnosis of inflammatory diseases using 150,000 daltons and binds to the carcinoembryonic antigen imaging modalities frequently employs imaging with ra (CEA),an epitopeon the granulocytesurfacethat is expressedat diolabeled leukocytes in addition to conventional methods the nonspecific cross-reacting antigen, NCA-95. The affinity con stant of the antibody is 2 x l0@liter/mol/granulocyte. The such as x-ray, CT, and radionuclide bone scanning (1— lyophilized antibody can be readily labeled with @mTcin a one 11). The aim of these diagnostic efforts is to detect and step procedure. The in vivo binding of AGAB to granulocytes is verify septic inflammatory disease as early as possible after greater than 90%. Granulocyte function is not altered, since there the initial clinical suspicion. is neither cell-mediated cytotoxicity nor complement-mediated cytotoxicity by antibody-binding to the granulocyte. The labeling procedure was as follows: The average activity to label one vial ReceivedAug.12,1991; revisionacceptedNov.21, 1991. For reprints contact: Andreas L Hotze, MD, Department of Nuclear Medi of lyophiized antibody for one patient was 500 MBq of 99mTc, csne,Universityof Bonn,Bonn5-300,Germany. and the labeling efficiency was >95% in all trials (thin-layer

526 The Journalof NuclearMedicine•Vol. 33 •No. 4 •April1992 chromatography). After a 10-mm incubation period, the labeled RESULTS antibodies were injected into the patient. Other workers have reported the development of HAMAs (human anti-mouse anti The diagnosis ofa septic (bacterial) bone infection could bodies)in 22% of all patientsafter an averageperiod of 7—8wk be established by surgery and histopathology in 9 of 20 following the injection ofAGAB (15). No side effects or adverse Group I patients (extremities) and in 5 of 10 Group II reactions following the injection were observed in any of our patients (spine). In 11 Group I patients and in 5 Group II patients. patients, an infection could be excluded by the subsequent Planar whole-body images were obtained 2 (early images) and clinical course. 4 hr and 20 to 24 hr (delayed images) postinjection, respectively, and 500,000 counts per image were collected. The scans were Patients obtained on a LFOV gamma camera equipped with an all purpose collimator connected to a computer (Apex 409 Group I (Patients with Suspected Osteomyelitis of the A, Elscint). Peripheral Bones, Table 2). In eight Group I patients, The normal antibodydistributionis characterizedby the vis AGAB accumulations were visualized on the bone scans. ualization of the entire bone marrow, liver and spleen (delayed These findings were in agreement with the final diagnosis images). In addition, blood-pool activity (e.g., major vessels) is ofosteomyelitis (eight true-positive scintigraphic findings). visible on the early images. Together with the results of the An example of a true-positive finding is illustrated in delayed images, the early images representing vascular structures Figure 1. were helpful in determining the effect of nonspecific blood-pool The AGAB studies revealed no abnormalities in seven radionuclide accumulation in the final evaluation of the respec patients and were finally considered to be true-negative tive scan. with respect to the clinical course. Three of these patients Allscintigramswereevaluatedbytwoexperiencedreaderswho were on oral antibiotic therapy at the time of scintigraphy. knew neither the results of other imaging modalities nor the Four AGAB scans showed antibody-leukocyte accu clinical status of the patients. Scans were considered positive for a bacterial (septic) infection when a focally increased antibody mulations that were interpreted as infectious lesions, but accumulation could be visualized. Only these findings were taken the clinical follow-up could not confirm the diagnosis of as positive findings for infection. So called “coldlesions―(e.g., osteomyelitis (four false-positive scintigraphic findings). defects) were considered negative for infection. Three of these patients were on oral antibiotic therapy at the time of scanning. These false-positive scans occurred in one patient with osteoporosis due to inactivity of the Patients Thirty-three patients were studied (23 male, 10 female), rang left kneejoint following trauma. One patient had a reactive ing from 15to 70 yr ofage with an average age of47 yr. Infection synovitis after hemarthrosis in hemophilia A (Fig. 2). The ofthe extremities was suspected in 23 patients (Group I), and 10 third patient had a (non-bacterial) synovitis of the talona patients were referred with suspected infection of the spine vicular joint, and the fourth patient had an acute attack (Group II) (Table 1). (episode) of Bechterew's disease with pain symptoms in Allpatientswhowerestudiedscintigraphicallyhad previously the right foot in which AGAB accumulation was noted. suspected spondylitis and osteomyelitis of the peripheral bones. In one patient with known chronic left coxitis, the Only those patients were included in the study for whom the AGAB scan showed a defect (cold lesion) at the left hip final diagnosis of osteomyelitis had been either established by joint (Fig. 3). This scan was considered negative. From histology, microbiology and radiology, or had been excluded from this patient's radiograph, a bone infection was suspected, a longstanding clinical course. The suspected areas were investi gated by planar x-ray in all patients and T-CT studies were and a joint puncture confirmed a bacterial infection by performed in 18 patients. All AGAB scans were evaluated at the time of scintigraphy without knowledge ofthe final diagnosis. TABLE lB Hence, by these criteria, 30 patients could be included into the Age of SuspectedInfectionand FinalScmntigraphicResults study who had a final diagnosis by means other than scintigraphic I. SuspectedPeripheralInfections(n= 20) methods (Group I: 20 patients, Group II: 10 patients). Years 0.5—1 1—3 3—5 >5 Finalresults T+ 3 2 — 3 TABLE IA T— 4 2 1 F+ 2 2 — Localization of Questionable Bone Infections F— — 1 — LocationandNumberof Lesions II.SuspectedCentralInfections(n= 10) ExtremitiesSpineHips4Thoracic3Knee Years 0.5—1 1—3 3—5 >5 Finalresults T+ — joint5Lumbar7Tibia3Foot6Femur3Humerus1Clavicula1Total2310 T— — 2 1 2 F+ — F— 1 1 1 2

T+; T—:true-positive;true-negative. F+; F—:false-positive;false-negative.

Technetium-99m-labeled Antibodies for Bone Infection •Hotze et al 527 TABLE 2 4h pi. Resultsfor GroupI Patients(n = 20) with Suspected Infection of Peripheral Bones scansFinal °@Tc-AGAB .- .(..;4. diagnosis* + — All .:@ FIGURE 2. False Septicinfection 8 1 9 positive @‘Tc-AGAB Nosepticinfection 4 7 11 scan. This patient with HemophiliaA I Total 12 8 20 (since1964)and HIV positive (since 1989) Sensitivity= 89%, specifIcity= 64%, accuracy = 75%, PPV = presentedwith corn 67%,andNPV= 88%. plaints of the left kneejoint.X-rayand * All diagnoses based on histopathology (biopsy or surgery) or on long-standingclinicalcourse. laboratory investiga +: Focallyincreased @1c-AGABaccumulation. tions showed normal findings. Left knee —: Normal findings on @Fc-AGAB scans. joint puncture re vealed an aseptic, re active synovitisfol the detection of enterococcus bacteria (one false-negative lowinghemarthrosis. RVL scan). From these results a sensitivity of 89%, a specificity of other had been diagnosed as having a healed tuberculotic 64%, an overallaccuracyof 75%, a negativepredictive spondylitis. value of 88% and a positive predictive value of 67% were Due to the study protocol, five AGAB scans were con calculated for AGAB scanning in patients with suspected sidered false-negative since there was not an increased but peripheral bone infections. a focally decreased activity detectable at the site of the Group II (Patients with Suspected Spondylitis, Table 3). suspected vertebrae. Of these five patients, one patient This group consisted of 10 patients with suspected spine presented with post-traumatic spondylitis, two with spon infections. Four of these patients were on antibiotic treat dylitis of unknown origin and two with tuberculotic spon ment at the time of scintigraphic investigation. The scm dylitis. Three patients were treated with antibiotics. All tigrams did not show increased AGAB accumulation at patients were finally diagnosed as having bacterial infec the site of the suspected infection in any of these patients. tion by surgery and histopathology. Five AGAB scans were true-negative, from which three patients were found to have slightly decreased AGAB Comparisonof GroupI andIIResults accumulation at the suspected vertebra. One of these pa For all patients (Table 4), the sensitivity of AGAB tients had a previously healed spondylitis, one a high-grade scanning to detect a septic infection was 57%, the specific (severe) osteochondrosis, and the third patient presented ity 75%, the accuracy 67%, and both the positive and the with a healing fracture. Septic infection could be excluded negative predictive value were 67%. in all of them by the subsequent clinical course and the Excluding patients with “coldlesions―,one could cal results of other (x-ray based) investigations. culate the following values: sensitivity and specificity: 89%, The remaining two scans showed no abnormalities (nor accuracy: 76%, positive predictive value: 67%, negative mal AGAB accumulation within the bone marrow). One predictive value: 89%. of these patients had a nonspecific spondylitis, and the For “coldlesions―as “true-positive―findings (despite the initial evaluation), the following values would have been calculated: sensitivity: 94%, specificity: 67%, accu

TABLE 3 Resultsfor GroupII Patients(n = 10) with SuspectedSpine Infections scansFinal @‘Tc-AGAB @ diagnosis' All FIGURE1. True positive @‘TC-AGAB Septicinfection 0 5 5 scan. This patient Nosepticinfection 0 5 5 had a history of ar throdesis of the Total 10 10 nght ankle joint and subsequent chronic pain. Biopsy re * All diagnoses based on histopathology (biopsy or surgery) or on vealed a chronic long-standingclinicalcourse. osteornyelitis. —:Slightly decreased activity and cold lesions.

528 The Journalof NuclearMedicine•Vol. 33 •No. 4 •April1992 TABLE 4 The in vivo distribution of@mTc@AGABis quite similar Results for Group I and II Patients (n = 30) to that of' ‘‘In-labeledleukocytes and visualizes the entire scans bone marrow RES as well as the liver and spleen RES —AllSeptic Finaldiagnosis+@‘Tc-AGAB (10). In contrast to leukocyte imaging using 99mTc infection HMPAO labeled white blood cells, no nonspecific activity 16Total121830SensitivityNosepticinfection8 46 1214 was observed within the gastrointestinal tract. AGAB im aging would thus be applicable for detection of possible abdominal infections. In a previous study (10), we corn pared inflammation imaging using antibodies, conven = 57%, specifici = 75%, accuracy = 67%, PPV = tional mixed white blood cells and nanocolloid in patients 67%,andNPV= 67%.ty with suspected peripheral infections. In this study, all three methods showed almost identical scintigraphic findings. We also attempted to establish a quantitative measure racy: 83%, positive predictive value: 8 1%, negative predic (e.g., count ratios between affected and nonaffected ex tive value: 89%. tremity, count ratio between lesion and background) All infectious lesions were clearly visualized on both the which would enable a differentiation between more acute early scans (4 hr p.i.) and the delayed scans (24 hr p.i.). or chronic infections. These attempts, however, failed to There were no changes in lesion activity patterns nor were provide a sufficient high correlation (31). there visible changes concerning the normal activity dis The visual comparison of the 4-hr and the delayed tribution between the 4- and 24-hr p.i. scans. AGAB scans in our study did not show significant differ ences of activity distribution (except blood-pool activity DISCUSSION on the early images) on either image so that a diagnosis The in vitro labeling ofAGAB with 99mTcwas easy, and could be sufficiently established from the scan taken 4-hr the entire labeling procedure required an average time postinjection. This situation has also been suggested by period of 20 mm. This short time period represents an Joseph and coworkers (16), who demonstrated all infected enormous advantage compared to the time-consuming lesions at 2—6hr following injection. procedure of blood cell isolation and labeling, as is neces For patients in our study, irrespective of peripheral or sary using the conventional ‘‘‘Inor 99mTc@HMPAO spinal infections, the sensitivity and specificity were rela methods. tively low with values of57% and 75%, respectively. These Bone and bone marrow scans were not part ofthe study results are in contrast to some former studies which re protocol since there were concerns that not all those mo ported a sensitivity of75%—lOO%and a specificity of 89%— dalities could have been performed within a time period 100% for detecting bone infections (17—21). sufficient to ensure an accurate comparison of the results. Using the data for those patients with peripheral infec In most of the patients, however, we performed either tions in our study, the sensitivity would be 89% with a bone or bone marrow scans, usually a couple of months specificity 64%. Even these values, however, are still lower prior to or after the time the patient entered the study. than those reported in the literature. We believe that these Since we designed a prospective blinded study to evaluate differences are not related to cell alteration in the labeling the significance of AGAB scanning, these results were not procedure. Bosslet et al. (21) recently demonstrated that included in this study. the in vivo affinity ofthe labeled antibody to granulocytes is absolutely specific and that the vital and functional properties of granulocytes are not altered by the immu A noreaction with the labeled antibody in vivo. These discrepancies may result from different imaging B―: agents and the selection of the patient groups since some authors still use the ‘‘‘Inand 99mTc-HMPAO in vitro labeling techniques (1 7,21). A major part of the data, @ if reported in the literature, however, was based on prese lected patients with bone infections prior to the scinti graphic study. Our study, in contrast, consisted of an unselected patient group, which means that the patients had not been referred with a previously known infection for AGAB scanning. We therefore believe that the results FIGURE 3. False-negative@“‘Tc-AGABscan(“coldlesion―)of of our study better reflect the ability of inflammation a patient with a history of suspectedspondylodiscitisand pain. X-rayandT-CT showeddestructionof lumbarvertebra2 and3 imaging with AGAB to detect a septic infection. andbiopsy-confirmedspondylitisandparavertebralabscesswith For the patients with suspected peripheral infections, E. coil bacteria. (A) Ventral view and (B) dorsal view. there were four false-positive scintigraphic results that

Technetium-99m-IabeledAntibodies for Bone Infection •Hotze et al 529 occurred in aseptic synovitis, Bechterew's disease and Os the spine, are based on a circumscribed fibrotic destruction teoporosis. Aseptic osseous and arthrogenous inflamma of bone marrow or decreased leukocyte migration due to tions as well as osseous healing processes can be accom the membranous wall of an abscess. panied by leukocyte and phagocytic cell accumulation In general, however, for the evaluation of a leukocyte which then leads to false-positive scintigraphic findings study, regardless of the agent used, one has to consider a using both labeled mixed cell preparations and in vivo completely different behavior of the labeled cells for pe labeled granulocytes. Previous studies also have reported ripheral and central infections. false-positive findings using ‘‘‘Inand @mTc@HMPAOla In conclusion, our results indicate that @mTc@AGABis beled mixed cell preparations(6, 23-27). Possible reasons not a suitable agent for detecting inflammatory diseases of for false-positive findings can be also seen in granulomas the spine. For questionable infections of the peripheral and in malignant tumors. We believe that the relatively osseous structures, 9@―Tc-AGABscintigraphy has a rela low specificity of AGAB scintigraphy does not allow for tively low specificity (64%) and a moderate sensitivity of the differentiation of an aseptic infection, nonspecific ar 89%. Thus, only unequivocal normal findings of periph thritis, osteotomy or fracture healing from septic bone or eral bones on the AGAB scan excludes a septic inflam joint infections. 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