Clinical indications, image acquisition and data interpretation for white blood cells and anti-granulocyte monoclonal antibody scintigraphy: an EANM procedural guideline

Clinical indications, image acquisition and data interpretation for white blood cells and... Introduction Radiolabelled autologous white blood cells (WBC) scintigraphy is being standardized all over the world to ensure high quality, specificity and reproducibility. Similarly, in many European countries radiolabelled anti-granulocyte antibodies (anti-G-mAb) are used instead of WBC with high diagnostic accuracy. The EANM Inflammation & Infection Committee is deeply involved in this process of standardization as a primary goal of the group. Aim The main aim of this guideline is to support and promote good clinical practice despite the complex environment of a national health care system with its ethical, economic and legal aspects that must also be taken into consideration. Method After the standardization of the WBC labelling procedure (already published), a group of experts from the EANM Infection & Inflammation Committee developed and validated these guidelines based on published evidences. Results Here we describe image acquisition protocols, image display procedures and image analyses as well as image interpre- tation criteria for the use of radiolabelled WBC and monoclonal antigranulocyte antibodies. Clinical application for WBC and anti-G-mAb scintigraphy is also described. Conclusions These guidelines should be applied by all nuclear medicine centers in favor of a highly reproducible standardized practice. . . . . Keywords Infection Inflammation Acquisition protocols WBC Monoclonal antibodies Introduction way images should be acquired and interpreted. It is not the aim of this guideline to compare the indication of different Scintigraphy using radiolabelled white blood cells (WBC) and nuclear medicine modalities and radiopharmaceuticals in clin- anti-granulocyte monoclonal antibodies (anti-G mAb) has ical practice. Several reviews are available for advanced and been used in a variety of different clinical situations [1, 2]. more comprehensive readings on the topic, including four While it is difficult to draw evidence-based statistical conclu- papers which have been recently published with meta- sions for some clinical applications, for other infectious pro- analysis of data collected between 1985 and 2005 on the clin- cesses the role of these imaging tools is well standardized, ical use of radiolabelled WBC as compared to other available with grade A or B levels of evidence. diagnostic techniques [3–6]. Here we summarize the most important clinical indications The main aim of these guidelines is to support and promote in which WBC or anti-granulocyte mAbs can be used and the good clinical practice. Nevertheless, guidelines are used in the * A. Signore Department of Nuclear Medicine, Rambam Health Care Campus, alberto.signore@uniroma1.it Haifa, Israel Department of Nuclear Medicine, Cambridge Biomedical Campus, Cambridge, UK Nuclear Medicine Unit, Department of Medical-Surgical Sciences and Translational Medicine, BSapienza^ University of Rome, Nuclear Medicine Department, Hospital Universitario de Bellvitge, Ospedale S. Andrea, Via di Grottarossa 1035, 00189 Rome, Italy Barcelona, Spain Department of Nuclear Medicine, Université Catholique de Louvain, Regional Center of Nuclear Medicine, Azienda Brussels, Belgium Ospedaliero-Universitaria Pisana, Pisa, Italy Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 1817 complex environment of a health care system with its ethical, plasma, and images at 20–24 h after injection are more economic, legal and other aspects that need to be taken into reliable than if using Sulesomab. Furthermore, consideration in each country. Besilesomab, being a murine antibody may induce produc- tion of human anti-mouse antibodies (HAMA) that must be Autologous WBC and anti-G-mAbs checked before performing the study and limit its use to one single administration in life. Sulesomab, being a Fab’ Autologous white blood cells (mainly neutrophils) can be fragment, does not induce HAMA production and can be 99m 111 radiolabelled ex-vivo using Tc-HMPAO or In-oxine re-used several times in the same patient, but it is licensed as described elsewhere [7, 8] using sterile conditions in in Europe only for peripheral musculoskeletal infections. accordance with national regulation on the production of medicines. The recent availability of disposable sterile Osteomyelitis and spondylodiscitis closed devices for WBC labelling (Leukokit® and WBC Marker kit®) [9], functioning as disposable mini-isola- Osteomyelitis (OM) is an infection of the bone and bone mar- tors, has enormously facilitated the labelling procedure row due to the presence of aerobic or anaerobic micro-organ- that, however, remains time consuming and requires with- isms, viruses and/or fungi. OM can represent a complication drawing 30–40 ml of blood from patient. Once injected of a systemic infection or can be an infectious process located i.v. in the patient, radiolabelled WBC migrate rapidly to primarily in the bone or surrounding tissue. Of particular clin- the lungs and, if not damaged, proceed to liver, spleen and ical relevance is the differential diagnosis between OM and the reticulo-endothelial system, including bone marrow. soft tissue infection in diabetic patients with Charcot foot or Approximately 1 h after injection, labeled cells further forefoot infections [13–15]. migrate to bone marrow and, in case of an infection, to The most frequent origin of primary OM is haematogenic but the infected tissue due to chemotactic attraction caused by the micro-organisms can also reach the site of infection directly biofilm and its soluble products. The rate of accumulation (in patients with exposed fractures or following surgical proce- of labeled cells in infection sites depends on the site of dures, as in sternal infections) or simply per continuitatem.The infection (cardio-vascular tissue may accumulate WBC haematogenic OM is often caused by gram positive micro-or- within a few hours and much more rapidly than peripheral ganisms, whereas fungi and mycobacteria frequently produce bones and CNS), on the virulence and extent of infection direct and chronic infections. The conditions that predispose to (some bacteria produce more chemotactic factors than primary OM include immunosuppression, previous radiothera- others and some chronic infections or abscesses may py, diabetes mellitus (diabetic foot), drug addiction and hema- show minimal accumulation of leukocytes at late time tological chronic disorders (e.g. sickle-cell anemia). Secondary points), on the type of pathogen (fungal infection may OM is most often associated with (open) trauma, surgery and attract less WBC than bacterial infections), on the as- especially prosthetic implants (see separate paragraph). sumption of antibiotic or steroid therapy (that may reduce OM can be classified as acute, subacute and chronic ac- bacterial virulence or leukocyte migration) and on the cording to the type of onset and clinical course. Patients with status of vascularization of the infected tissue (capillaries acute OM usually present with fever, leukocytosis, elevated in the vertebral body may be compressed by oedema in acute phase reactants (ESR and CRP) and mild or intense pain case of spondylitis thus preventing WBC accumulation as in the affected region. Redness, pain, swelling and impaired well as capillaries in diabetic patients with micro-macro function (the classic rubor, tumor, dolor, calor, function laesa angiopathy/neuropathy or in patients with severe athero- as described by Galen) may also be present. sclerotic lesions). The diagnosis of OM can be challenging. Radiological With the aim of simplifying the procedure of WBC la- techniques, such as computed tomography (CT) and magnetic belling, some anti-granulocyte monoclonal antibodies have resonance imaging (MRI) play an important role, been described. Two products are commercially available: complemented by radionuclide imaging procedures (mainly a whole murine IgG anti-NCA-95 antibody (Besilesomab, radiolabelled white blood cells with nanocolloid scan for bone Scintimun®) [10], and a Fab’ fragment anti-NCA-90 marrow imaging, but also anti-G-mAb scintigraphy) with an (Sulesomab, Leukoscan®) [11]. Both radiopharmaceuti- overall accuracy that exceeds 90% [12, 16–22]. cals bind to peripheral neutrophils but with substantial Radiolabelled WBC is not a valid radiopharmaceutical for biodistribution differences [12]. Besilesomab accumulates the diagnosis of vertebral infections, the frequent lack of up- more than Sulesomab in normal bone marrow, but binds take in the site of infection, as well as in other benign spine more efficiently to neutrophils in blood and at sites of pathology, does not allow for accurate diagnosis or useful infection. It has lower plasma disappearance than follow-up. [ F]FDG PET/CT in association with MRI pro- Sulesomab, thus mimicking the biodistribution of vides the highest diagnostic accuracy [23–26]. Nevertheless, radiolabelled autologous WBC. It is also more stable in in early spondylodiscitis (within 1 week from onset of 1818 Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 symptoms) and in para-vertebral soft tissue infections associ- extramural complications such as abscesses, fistula and perfo- ated with spondylodiscitis, WBC scan can be used. rations [31]. These techniques therefore usually are the first Clinical indications for nuclear medicine evaluation: choice imaging methods due to their availability and good accuracy. WBC scintigraphy allows additional information Peripheral bone osteomyelitis (OM) to be obtained regarding the degree of activity of disease and Suspected OM its extent [31, 32]. There are some limitations to labeled WBC Evaluation of extent of OM imaging in IBD. The test cannot identify anatomical changes Evaluation of treatment response such as strictures, which are best delineated with endoscopy Spondylodiscitis and contrast radiography. It is less sensitive for disease affect- Para-vertebral soft tissue infection in spondylodiscitis ing the upper tract than the lower gastrointestinal tract and may also be affected by steroid administration [32, 33]. Clinical indications for nuclear medicine evaluation: Joint prosthesis and other orthopedic hardware & Evaluation of activity of disease More than a million hip replacements are performed each year & Evaluation of extent of disease worldwide, and the number of other artificial joints (shoulder, & Differential diagnosis between inflammatory and fibrotic elbow, hip, knee) inserted is also rising. With increasing num- strictures bers of implantations, mechanical and infected loosening of & Early assessment of disease relapse after surgery the prostheses have become more common. The risk of infec- & Evaluation of treatment response tion is highest during the first two years after implantation. Differentiating infection from aseptic loosening is difficult because the clinical presentation and the histopathological changes in both entities can be similar, but at the same time Fever of unknown origin is extremely important because the treatment of these two entities is different. Joint aspiration with gram stain and cul- Fever of unknown origin (FUO) is defined as a body ture is considered the definitive diagnostic test; its sensitivity, temperature higher than 38.3 °C persisting for two weeks however, is variable, ranging from 28 to 92%; specificity is or more, remaining unexplained after 3-day inpatient or more consistent, ranging from 92 to 100%. Plain radiographs two-week outpatient observation. Beside the classical are neither sensitive nor specific and cross-sectional imaging ‘pure’ FUO, Durack identified related conditions modalities (CT and MRI) are limited by hardware induced encompassing neutropenic FUO, HIV-associated immune depression FUO and nosocomial FUO [34]. Diagnosis is artifacts. Radionuclide imaging (both WBC and anti-G-mAb scintigraphy) that is often not affected by metallic hardware often made by a good anamnestic assessment with special can play an important role in the diagnosis of prosthetic joint attention to occupational and recreational exposure to infection. The evaluation of hybrid images (SPECT/CT) can pathogens, a recent travel history or drug abuse. be also performed after imaging reconstruction without atten- Laboratory tests are also relevant but may be very unspe- uation correction, with an overall accuracy ranging from 88 to cific and radiological imaging may be helpful although in 98% (being highest for WBC combined with bone marrow most cases the origin of FUO remains uncertain [34]. imaging) [21, 27–30]. Scintigraphy with labeled WBC and PET with [ F]FDG Clinical indications for nuclear medicine evaluation: are additional imaging modalities to evaluate patients with FUO with high sensitivity, thus a negative study virtually ex- & Suspected septic loosening cludes an infection as the cause of the fever [35–38]. It is & Evaluation of extent of infection accepted that when patients with FUO have low probability & Evaluation of treatment response of infection (low ESR, WBC count and CRP) the first scan to & Suspected infective post-traumatic pseudo-arthrosis be performed should be [ F]FDG. If patients have a high & Exclusion of infection in patients with antibiotic spacer clinical probability for infection they should first perform a before prosthesis re-implant WBC scan. There are also reports on the use of radiolabelled anti-granulocyte mAb in FUO with comparable diagnostic accuracy as for WBC. Inflammatory bowel diseases Clinical indications for nuclear medicine evaluation: Inflammatory bowel diseases (IBD) mainly include Crohn’s & Evaluation of unknown site of infection in patients with Disease (CD) and Ulcerative Colitis (UC). Ultrasound (US), high pre-test probability of infection CT and MRI are of particular use in evaluating the presence of & Evaluation of extent of disease Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 1819 Soft-tissue infections pulmonary uptake is caused by technical artifacts caused by faulty labelling or reinjection and is usually not associated Postoperative infections Nuclear medicine procedures can be with infection and disappears within 4 h post injection. a useful adjunct to morphologic imaging and can facilitate the Clinical indications for nuclear medicine evaluation: differentiation of abscesses from other fluid collections, tu- mor, and normal postoperative changes. Labeled WBCs rarely & Diagnosis of bacterial pneumonia accumulate in uninfected tumors and do not, with few excep- & Differential diagnosis of infective and neoplastic lesions tions, accumulate in normally healing surgical incisions & Evaluation of treatment response [39–41]. Consequently, because of this high specificity, WBC imaging is the preferred radionuclide test for the evalu- ation of postoperative infections [42]. Central nervous system infections The differential diagnosis of a contrast enhancing brain lesion identified on CT or MRI Cardiovascular system infections Echocardiography is readily includes abscess, tumor, cerebrovascular accident, and even available and accurately diagnoses bacterial endocarditis. multiple sclerosis. WBC scintigraphy provides valuable infor- Nevertheless, the use of radiolabelled WBC scintigraphy accu- mation in the differential diagnosis of contrast enhancing rately detects infective endocarditis and extra-cardiac septic brain lesions [55–61] and in the follow-up of patients with embolisms [43–47]. Prosthetic vascular graft infections are also malignant otitis. False negative results have been reported in first studied by angio-CT, and labeled WBC imaging is a useful patients receiving high doses of steroids [61]. The use of anti- complement [48–52]. The accuracy of WBC imaging for diag- G-mAb can also be useful in these situations [62, 63]. nosing prosthetic vascular graft infection is above 90%, and the Clinical indications for nuclear medicine evaluation: use of [ F]FDG is also a highly accurate alternative [53]. No role of WBC scan has been suggested for imaging vasculitis. & Cerebral hypodensity CT lesions with hypervascularized Clinical indications for nuclear medicine evaluation: peripheral ring & Differential diagnosis of cerebral lesions in HIV patients Infective endocarditis (IE) Suspected IE with doubtful ultrasound Evaluation of septic embolism in certain IE Other applications of radiolabelled WBC and mAbs Evaluation of treatment response Differential diagnosis with marantic vegetations Aids WBC scintigraphy plays a limited role in the evaluation of Vascular graft infections AIDS-related infection. The test is not as sensitive as CT for Diagnosis of infection detecting opportunistic infections of the lungs and lymph nodes. Evaluation of extent of disease The test is useful, however, for detecting colonic infections in Evaluation of disease activity the HIV(+) patient [64–66]. It must be kept in mind that han- Evaluation of treatment response dling blood from HIV-infected patients carries a risk for both the staff and fellow patients if multiple labelling procedures are performed at the same time, and recommendations regarding Pulmonary infections Although pulmonary uptake of labeled this specific issue have been previously published [1, 67, 68]. WBC is a normal event during the first few hours after injec- tion, its appearance after 24 h is abnormal. Diffuse pulmonary activity on images obtained more than Image acquisition protocols 4 h after injection of labeled WBC can be due to opportunistic infections, radiation pneumonitis, pulmonary drug toxicity The use of anti-G-mAb and WBC scintigraphy has many use- and adult respiratory distress syndrome. A diffuse pulmonary ful fields of application. Nevertheless, the image acquisition uptake pattern is also seen in septic patients with normal chest protocols are not always identical, and in addition, there may radiographs who have no clinical evidence of respiratory tract be some variation in the criteria used in image interpretation. It inflammation or infection. It is important to note that while is therefore important to standardize, based on published evi- diffuse pulmonary activity on labeled WBC images is associ- dence and on the experience of the authors, the acquisition and ated with numerous conditions, it has been only very rarely interpretation protocols for each disease. Therefore, the aim of described in bacterial pneumonia [54]. Focal pulmonary up- this guideline is to provide general recommendations for im- take that is segmental or lobar is usually associated with bac- proving clinical practice and to minimize the occurrence of terial pneumonia. This pattern can be also seen in patients with artifacts and interpretation hurdles. cystic fibrosis and is due to WBC accumulation in pooled For all studies using labeled blood products, it is essential secretions in bronchiectasic regions. Non-segmental focal that measures are in place for correct patient identification in 1820 Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 99m order to avoid cross-administration of labeled cells to the For Tc labeled anti-granulocyte mAbs scintigraphy ear- wrong patient [7, 8]. ly lung images are not necessary but (as applicable) planar, The potential interference of some drugs and antibiotics SPECT (or SPECT/CT) and whole-body images at 3–4hand with cell labelling has to be considered [67, 68]. However, 20–24 hshouldbe performed. patients receiving antibiotic treatment should not be excluded According to different biodistribution of labeled WBC in Bapriori^ since reports regarding their effect on WBC scin- blood, bone-marrow, infection and sterile inflammation, three tigraphy give various results. While several authors describe sets of images must be generally acquired of the region of no interference between such treatment and the accuracy of interest: Bearly images^ (within30 minand1hp.i.), Bdelayed WBC/mAbs scanning, others advise delaying the scan for at images^ (between 2 h and 4 h p.i.) and Blate images^ (between least 1–2 weeks after therapy withdrawal or, in the case of 20 h and 24 h p.i.). Early images provide useful information doubtful study results in patients receiving antibiotics, to re- on the lung transit, on liver/spleen ratio (which should be at peat the test 2 weeks later. The decision whether to perform or least 1:2 but may also depend on the neutrophil:eosinophil cancel the study depends entirely on the clinical setting and ratio since neutrophils preferentially migrate in the liver and must be discussed case-by-case with the referring physician. eosinophils; that uptake HMPAO much more avidly than neu- trophils, preferentially migrate in the spleen) on bone marrow 99m Acquisition protocols for Tc-labeled WBC and anti-G-mAb distribution and on vascular pattern. Sites of infection should scintigraphy be visible on delayed images with further accumulation of labeled leukocytes seen in the late images due to increased A large-field-of-view gamma camera with a low-energy high- uptake in infected areas and reduction in background activity. resolution collimator should be used. Camera resolution Over time there is also reduction or stable activity in bone should always be set to zoom 1 at 512 × 512 pixels with a marrow and non-specific activity in the bowel due to Tc- HMPAO excretion from the liver. high resolution collimator. 99m For Tc labeled WBC studies, an in vivo quality control Several acquisition protocols have been suggested for both 99m Tc-labeled WBC and anti-G mAb scintigraphy. Fixed should be performed including imaging of lungs, liver and spleen at 30 min post-injection (p.i.) (early images). Normal counts per image or fixed times per image at all time points bowel activity is seen in 20–30%of children at 1hand 2–6% are the most commonly used protocols but also the most dif- of adults at 3–4 h p.i. According to the clinical indication, ficult to be interpreted because of interference of radioactivity whole-body, planar and, if appropriate, SPECT (or SPECT/ from other organs and operator bias in image display. For CT) images should be performed at 3–4 h (delayed images) fixed counts or time acquisitions, images of the regions of and 20–24 h (late images). interest are acquired for at least 500,000 counts or 5–10 min 99m 111 Table 1 How to calculate acquisition time according to decay of Tc (A) and In (B) a 99m Hours Acquisition time (seconds) for Tc decay corrected images exp(-λt) λt 0 100 150 200 300 (Early images) 1 112 168 224 337 0.8909 0.1155 2 126 189 252 378 0.7937 0.231 3 141 212 283 424 0.7072 0.3465 4 159 238 317 476 0.6300 0.462 6 200 300 400 600 0.5001 0.693 8 252 378 504 756 0.3969 0.924 14 504 756 1008 1511 0.1985 1.617 20 1007 1511 2015 3022 0.0993 2.31 22 1269 1904 2538 3808 0.0788 2.541 a 111 Hours Acquisition time (seconds) for In decay corrected images exp(-λt) λt 0 100 200 300 400 (Early images) 1 101 202 303 404 0.9897 0.0103 2 102 204 306 408 0.9795 0.0206 3 103 206 309 413 0.9694 0.0310 4 104 208 313 417 0.9595 0.04137 6 106 213 319 426 0.9398 0.06205 8 109 217 326 435 0.9206 0.08274 14 118 236 354 472 0.8475 0.16549 20 123 246 369 492 0.8131 0.20686 22 125 250 374 499 0.7965 0.22755 Time 0 is the time of the first scan not necessarily the time of injection Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 1821 with a large field of view including a region of normal bone producing false positive images at later time points. Only in marrow as a reference (e.g. iliac bone, sternum or skull). cases with a suspected fistula or abscess it is necessary to These methods, and particularly the acquisition of several acquire images at a later time point, at 4–6 h after radiophar- images at several time-points with the same amount of counts, maceutical injection (or even 20–24 h post injection). This is discouraged or recommended for expert readers. pitfall does not occur with In-labeled WBC that are there- In order to reduce operator dependence in image display fore preferable for studying abdominal infections. For the 99m and final interpretation, we recommend acquiring images same reason, when using Tc-labeled WBC, vascular graft time-corrected for isotope decay (see Table 1). If early images infections of abdominal vessels (aorto-bi-iliac grafts) should are acquired with a set number of counts or time, delayed and be imaged within 3 h from administration of labeled cells. A late images should be corrected for the isotope half-life. With dynamic acquisition (one image every 5 s for the first 150 s this acquisition modality, different images can be compared after injection) may help to map the vascular structures and with the same intensity scale, in absolute counts (and not in % detect obstructions or aneurisms. For all these intra-abdominal of maximum activity) thus avoiding any operator bias [1]. and pelvic infections, SPECT/CT can be extremely helpful (if This method also allows to correctly detect a true increase of not mandatory), allowing for a precise localization of an infec- uptake in suspected regions over time, an important criteria of tious focus to the vascular graft or adjacent soft tissues only. positivity for bone infections and for most soft tissue infec- With anti-G-mAbs, image protocols differ between com- 99m tions. The method has been recently validated in a multicentre plete and fragmented antibodies: images with complete Tc- European study [69, 70] as being highly accurate for osteo- anti-NCA-95 antibody should be performed at 2–4 h p.i. and myelitis, prosthetic joint infections, diabetic foot osteomyelitis 16–24 h p.i. in planar whole body technique because a signif- and some soft tissue infections (such as dermal filler infec- icant increase in sensitivity and specificity will be achieved tions, endocarditis, abscesses, brain infections and sternal with delayed 24 h images due to higher target to background wound infections) but not for soft tissue infection in diabetic ratios (T/B). Planar images can be performed with an acquisi- foot [14, 71]. tion protocol time-corrected for isotope decay, as mentioned SPECT or SPECT/CT is useful in most types of infection above for WBC. The best time point for SPECT images is 4– but should be considered mandatory in a few selected indica- 6 h after injection but another SPECT at 16–24 h p.i can also tions (e.g. endocarditis, diabetic foot, vascular prosthesis). If be performed if required, similarly to WBC scan. 99m SPECT or SPECT/CT is used for quantitative purposes, this With Tc-anti-NCA-90 (Fab’) antibodies, images should should be acquired in a 128 × 128 matrix utilizing the same be performed 1 h p.i. and 4–6 h p.i. in whole body as well as in decay-corrected protocol as described above (i.e. 5 h post- single scan technique. Acquisition protocols are also better injection for 7 s/step and 20 h post-injection for 40 s/step, using time-corrected for isotope decay. SPECT of suspected because of 15 h difference between the two scans). If acquired central bone infection should be performed at 4–6 h p.i., with a decay-corrected protocol, SPECT images can also be whereas in case of suspected endocarditis delayed SPECT used for semi-quantitative purposes to evaluate any increase images at 16–24 h p.i. have also been suggested [45]. The 99m of T/B ratio with time. combination of Tc-anti-NCA-90 (Fab’) antibodies and 99m Typically, however, a SPECT/CT is performed after planar Tc-HDP three phase bone scan can be useful to rule out images (4 or 5 h post injection) only to provide the best ana- false positive accumulation of the antibody fragment due to tomical localization of WBC accumulation, but the positivity non-specific inflammatory oedema. Others have suggested for infection is given by comparing delayed and late planar also performing late images 20–24 h after injection to improve images. Therefore, the SPECT/CT is not required for semi- the specificity [72, 73], although this protocol and the speci- 99m quantitative purposes and acquisition at 4–5 h p.i. can be ac- ficity of Tc-anti-NCA-90 (Fab’) antibodies have been crit- quired with 20–30 s/step (depending on the injected activity) icized by others [74, 75]. and acquisitions at 20–24 h p.i. are often not necessary (even For both antibodies, as for labeled WBC, SPECT/CT because would require a very long acquisition time) but can be should be considered mandatory for endocarditis, diabetic foot also performed if new sites of pathological uptake appear that and vascular prosthesis. were not detected at 4–5 h scan (in this case acquisition time should be at least 30–50 s/step, also depending on the injected Acquisition protocols for In-labeled WBC scintigraphy activity and on the region to be imaged, with time longer for peripheral parts and shorter for the abdomen). A large-field-of-view gamma camera with a medium energy 99m 111 When using Tc-HMPAO-labeled WBC for abdominal collimator should be used. Both In photopeaks should be infections and IBD, images should only be acquired at 30 min acquired at 173 and 245 keV (±10%). If using a time-saving 99m and 2–3 h after injection of the labeled WBCs. This is because acquisition protocol with both Tc-colloid for bone marrow 99m 111 a metabolite of Tc-HMPAO is released by WBC with time, imaging performed in orthopedic cases prior to In-WBC re- taken up by the liver and excreted via the bowel, thus injection, only the upper peak of In should be subsequently 1822 Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 99m acquired (245 keV) to avoid cross-contamination of Tc performed at the end of the WBC/mAb study (same day of the into the lower peak of In. This will obviously reduce the 24 h image or in the next few days) by injecting i.v. about 99m statistics but improve the specificity [28, 29]. 185 MBq (5 mCi) of Tc-colloids (colloids of greater than Images of the chest, abdomen and pelvis should be obtain- 500 nm are recommended) and acquiring images of the region ed for at least 100,000 counts but images over the peripheral of interest after a minimum of 20–30 min and a maximum skeleton may be acquired for time. As described above for time of 6 h p.i. Images should be performed of the same views 99m Tc, time presets decay-corrected can be used (see Table as those acquired with WBC/mAbs although the acquisition 99m 1), although they are less relevant than for Tc due to the time should be limited to 300 s (if performed immediately at 111 111 long half-life of In. As In-WBC scintigraphy is prefera- the end of WBC/mAbs scan) or 500,000 counts (if performed ble in low-grade infection, delayed and late imaging is usually one or more days after WBC/mAbs scan). Another option in 99m sufficient and is not impaired by elution of the radiolabel from patients with violated bone is to perform Tc-colloid mar- WBC. In abdominal infections or IBD, early imaging may be row imaging simultaneously with WBC scans if labelling is 111 111 useful to differentiate between mucosal uptake that will de- done with In-oxine/tropolone. In this case, during In- crease with time with intraluminal transit, sub-mucosal uptake WBC imaging only the upper peak of the In emissions that remains stable, and abscess that will show increasing should be used [28]. uptake between 3 and 4 h and 20–24 h p.i. Given the low statistics due to the limitations in the injected activity for do- Interpretation criteria for WBC and anti-G-mAbs simetry reasons, SPECT or SPECT/CT may have to be per- formed with prolonged acquisition times. The very low back- Given a correct acquisition protocol, images must be correctly ground activity will nevertheless allow high contrast with such displayed on the screen to allow their correct interpretation. acquisition settings, even with low statistics. When using In-labeled WBC for IBD evaluation, stool Most work stations are pre-set to display multiple images in % of maximum counts/pixel. This display does not allow the collection and counting at early and late time point may indi- cate the presence of radiolabelled cells migrating from infect- reader to evaluate modifications of activity with time in the regions of interest. Furthermore, this kind of display needs the ed mucosa to the lumen, an indirect sign of inflamed bowel. Planar acquisition of the pelvis in outlet views (namely, with reader to adjust the intensity scale of each image to make bone marrow activity comparable and therefore introduces an oper- the patient sitting above the gamma camera) or SPECT/CT may discriminate better between rectal and bladder activity in ator bias [1, 69, 70]. All images acquired at different time points must be case of suspected recto-sigmoidal extent of IBD [32, 33]. displayed with the same intensity scale in absolute counts, when they have been acquired with a time-decay corrected Acquisition protocol for bone marrow scintigraphy (for bone protocol. Any adjustment of the intensity scale must be ap- and prosthetic joint infection) plied to all images together, thus avoiding any operator bias. Further interpretation of labeled WBC/mAb scintigraphy Bone marrow scintigraphy is usually performed in doubtful requires knowledge of the normal variants and pitfalls of these WBC scans for bone and prosthetic joint infections. These are studies. The normal biodistribution of the Table 2 Normal biodistribution of radiopharmaceuticals 99m 99m 99m 111 99m Location Tc-WBC Tc-WBC Tc-WBC In-WBC Tc-mAbs early (30′-1 h) delayed (3-4 h) late (20-24 h) (3 h/24 h) (3 h/24 h) Blood/heart +++ + – ±± Lung + –– −/−−/− Liver ++ ++ ++ ++/++ +++/+++ Spleen +++ +++ +++ +++/+++ +/++ Kidneys + + + −/− +/+ Bladder – ++ −/− +/+ Bowel – +++ −/− −/− Bone marrow + ++ ++ ++/++ +++/+++ a 111 With In WBC any bowel activity is abnormal; swallowed neutrophils from upper and lower respiratory tract could be considered in some cases of mild bowel activity Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 1823 radiopharmaceuticals has been summarized in Table 2,with Since labeled WBC and anti-G-mAb scintigraphy have a uptake ranging from – (no activity) to +++ (the most intense very high sensitivity, a negative scan (when there is no in- activity). Diagnosis of infection is made by comparing de- creased uptake of WBC with time) is sufficient to exclude layed (3–4 h) and late images (20–24 h). the presence of bone infection. Images are then classified as (a) negative, when there In case of equivocal qualitative analysis, a semi-quantitative is no uptake or there is a clear decrease of activity from analysis should be performed, and only in case of equivocal delayed to late images in the regions of interest, (b) quantitation (less than 10% increase of T/B over time) bone positive, when a clear increase is seen with time of up- marrow imaging must be used. Colloids, anti-G-mAbs and la- take intensity or size in the regions of interest, and (c) beled WBC accumulate in healthy and displaced bone marrow, equivocal, in all other situations. For OM in general, the whereas, in infection sites, colloids do not accumulate. early images at 30 min p.i. should be considered as a The WBC or anti-G-mAb scintigraphy is positive for Bvascular/bone marrow phase^.Itis usefultocompare osteomyelitis when there is activity on the primary scan it with the distribution of bone marrow. It must therefore without corresponding activity on the bone marrow im- be seen as a qualitative image and not considered for age. When any other pattern is present, the study is neg- quantitative analysis compared to delayed and late im- ative for infection [13, 28, 69]. ages [1, 69, 70]. There are sufficient evidence based data to support the use There might be several reasons for defining a set of images of both WBC and anti-G-mAb for the diagnosis of PJI and as Bdoubtful^. These are: similar or slightly decreasing uptake OM as well as for FDG-PET/CT, only for OM and not for PJI. with time in the regions of interest (intensity or size); increase One particular mention deserves the diagnosis of ster- of bone marrow with time that does not allow to easily eval- nal wound infections (SWI) after thoracotomy and the uate suspected regions; slight increase in size over time with- criteria for the differential diagnosis between superficial out an increase in intensity of uptake; slight increase in size infection (that requires medical treatment) and deep infec- and/or intensity over time in the region of interest but with a tion (that may require surgical treatment). In particular, if similar increase over time of bone marrow activity; activity in planar images at 3 h and 20 h are considered, a linear region of interest that remains unmodified with time (in size homogeneous uptake that decreases with time or remains and/or intensity) with bone marrow activity that increases or stable over time can be considered as no infection or su- decreases over time. perficial infection. An inhomogeneous uptake with areas In all doubtful cases, following visual assessment, a semi- of increased uptake over time can be considered as an quantitative evaluation can be performed for the differential infection, most likely a deep infection and rarely a super- diagnosis of infection from non-specific uptake [69, 71, 76, ficial infection. SPECT/CT acquisition can also be of help for the correct evaluation of the extent of infection. 77]. Regions of interest (ROIs) are drawn over the area of interest (usually with the highest uptake) and copied to a pre- sumed normal reference tissue; contra-lateral bone is the best Diabetic foot (DF) In diabetic foot, to identify a Charcot foot an when available [69]. The mean counts per pixel in these ROIs additional scan with colloids for bone marrow imaging is are recorded and used to calculate the lesion-to-reference (L/ mandatory to differentiate between expanded bone marrow R) ratio in both the delayed and late images (L/R and L/ (a common finding after many surgical interventions to the delayed R , respectively). When the L/R ratio increases with time (L/ bone as well as in Charcot foot) and OM [13, 14, 28]. There late R >L/R ) by at least 10%, the study can be considered are sufficient evidence based data to support the use of both late delayed indicative of infection; when the L/R is similar or decreases WBC and anti-G-mAb for the diagnosis of DF as well as for late slightly with respect to L/R the examination can be clas- FDG-PET/CT. delayed sified as equivocal; and when L/R is significantly decreased late compared to L/R (L/R <L/R ) the examination Inflammatory bowel diseases (IBD) Radiolabelled autologous delayed late delayed can be classified as negative for infection [69, 76]. WBC are a second-line imaging technique in IBD diagnosis If SPECT/CT is performed the delineation of the site of used in case radiological and/or endoscopic exams are incon- increased radiopharmaceutical uptake may be calculated by clusive [31]. The absence of abdominal uptake of WBC ex- a 50% isocontour on a single transaxial slice that shows the cludes the presence of IBD while the presence of pathological site with the highest uptake (the lesion) and the reference uptake can be due to IBD or to other disorders. WBC scintig- normal tissue. The same criteria as described above can be raphy is positive when there is an increase of uptake of WBC used for imaging classification. in delay images (2–3 h p.i). Differential diagnosis between UC and CD is possible according to the pattern and localisation of Prosthetic joint infection (PJI) and peripheral bone osteomy- the WBC uptake: if the uptake is in the ileo-cecal area, in the elitis (OM) The above described criteria should be used for the small bowel and there is a patchy distribution of radioactivity, it is more indicative of CD. Otherwise, when the leukocytes diagnosis of peri-prosthetic joint infection and osteomyelitis. 1824 Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 uptake is focused in left colon up to the rectum, or diffuse Fever of unknown origin (FUO) Labeled WBC scan is usually uptake in the colon, it is more characteristic of UC. If there adopted as second-line diagnostic investigations in the diag- is a colon uptake alone, it is not possible to establish a certain nosis of FUO, even if their overall performance is very satis- differential diagnosis. Major indications for WBC scan in IBD factory. The pre-test probability of infection is important and patients are: the early assessment of recurrences after surgery in case of low pre-test probability of infection (based on rou- and the differential diagnosis between inflammatory and fi- tine blood tests) an FDG-PET/CT scan is the preferred choice. brotic strictures, the first being positive and the second nega- In case of high white blood cell counts, ESR or CRP values a tive. There are no sufficient evidence based data to support the WBC scan can be performed as first imaging modality. use of anti-G-mAb scan in IBD. Indeed, due to high sensitivity and specificity of WBC scin- tigraphy (60–85% and 78–94%, for In-oxine; 96 and 92% 99m Vascular graft prosthesis infection (VGI) Radionuclide imag- for Tc-HMPAO), this can be considered the procedure of ing studies are usually complementary to radiologic im- choice in patients with FUO with high probability of infection aging, and limited to those patients with equivocal con- [78–80]. By contrast, there are no sufficient evidence based 99m ventional imaging. Tc-HMPAO-WBC scintigraphy has data to support the use of anti-G-mAb scan in FUO. Image shownveryhighsensitivityand specificity in the evalua- interpretation criteria depends on the region of pathologic up- tion of vascular prosthesis infection based on the presence take of the labeled WBC, according to that mentioned above. of pathologic accumulation of labeled WBC in the site of infection as early as 2–3 h post-injection [49]. As previ- Pulmonary infections (PI) There are too few reports (mainly ously described, early dynamic images and oblique im- case reports or AIDS patients) to define a specific imaging ages are useful integration to antero-posterior whole body protocol for pulmonary infections. Planar antero-posterior im- scans, but SPECT or SPECT/CT images are often manda- ages are generally sufficient, given the considerations and pit- tory to discriminate the exact location of any suspicious falls mentioned above. uptake seen in planar images. There are sufficient evidence based data to support the use Central nervous system infections (CNS) Scintigraphy with of both WBC and of FDG-PET/CT in VGI. radiolabelled WBC has shown to be very sensitive and spe- cific in CNS infections and other head and neck infections Infective endocarditis (IE) Nuclear medicine imaging tech- such as malignant otitis, sinusitis, dermal filler infections niques may be of great value in cases of undetermined echo- and skull osteomyelitis [55–63, 71]. Due to high physiological cardiographic findings (i.e., artifacts deriving from mechani- brain uptake of FDG, to date, WBC scintigraphy is the only cal prosthesis) in the suspicion of an infective endocarditis and and most accurate nuclear medicine technique for H&N infec- in detecting septic embolism (ref EHJ). Scintigraphy with la- tions. Planar antero-posterior images and latero-lateral images beled WBC should be performed always with SPECT/CT are often sufficient but SPECT and SPECT/CT acquisitions acquisition that enable obtaining high resolution images of can be mandatory in some low grade infections [71]. the thorax. When there is a progressive accumulation of Image acquisition protocols and interpretation criteria are WBC in the cardiac region (for example, valve leaflets) the summarized in Tables 3, 4 and 5. scintigraphy is positive. WBC scintigraphy is negative when there is no pathological uptake of WBC in the cardiac region Additional strategies that may improve accuracy while it is equivocal when there is a stable or decreasing ac- cumulation of labeled cells. Since two SPECT acquisitions If SPECT/CT is not available SPECT WBC or anti-G-mAb must be performed (usually at 5 h and 20 h post-injection) images can be co-registered with separately acquired CT or the acquisition time of each examination can be calculated MRI images (usually transaxial slides) for a more accurate according to isotope decay, in order to have the same statistics localization of the pathological uptake, but attention should in both images and avoid operator bias in the interpretation of be paid to the fact that thickness of SPECT and CT slides is findings. Total body scans at 3–4 h and 21 h post-injection different. (before and after SPECT acquisitions, respectively) should New software is also available for SUV calculation on also be performed to detect possible septic embolisms [2, SPECT images. 46, 47]. For prosthetic valves, it is important to analyze both CT-attenuated and non-attenuated (NAC) images since the Physiologic biodistribution, pitfalls and artifacts positivity at NAC excludes a false positive finding due to metallic artifacts. After in vivo administration of radiolabelled WBC, the cells There are sufficient evidence based data to support the use normally show a transitory migration to the lungs of both WBC and FDG-PET/CT for IE but not for the use anti- (margination) and then accumulate in the spleen and, to a G-mAb. lesser extent, in the liver and bone marrow, with a maximum Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 1825 Table 3 Summary of acquisition/interpretation protocols of musculoskeletal infections Examination Acquisition protocol Image interpretation Pitfalls Osteomuscular Labeled WBC and Qualitative analysis: Assess timing after surgical procedure. 99m (osteomyelitis, Tc-mAb-anti-granulocy- Infective lesions show an uptake that arise over Assess the presence of artifacts related to the and prosthetic tes: time while aseptic flogistic lesions show a attenuation over-correction in patients with joint infection) 30 min p.i. planar images for decreasing uptake over time. In doubtful cases metallic devices QC and ROI it is necessary to compare the images with 99m -3-4 hp.i.total-body and pla- Tc-sulfur colloids: infective lesion shows a nar images ROI mismatch pattern of radiopharmaceutical 20-24 h p.i.: planar and uptake. SPECT(/CT) ROI Semi-quantitative analysis: 99m - Tc-sulfur colloid Calculate the target/background ratio drawing 20–360 min p.i. planar images ROI on the regions that show an increased ROI uptake over time (T) and on contralateral bone marrow (B) FP results can be obtained if the scintigraphy is performed within 3–4 months after surgery 99m Discitis, spondylitis Tc-HDP/MDP: Clinical history (timing from surgical procedure, Assess timing after surgical procedure. and i.v. injection during dynamic and type of metallic implant, etc). Assess the presence of artifacts related to the spondylodiscitis acquisition Anatomic location of tracer uptake. attenuation over-correction in patients with 99m 67 4 h p.i. total-body, planar and Tc-HDP/MDP + Ga-citrate: metallic devices SPECT(/CT) images ROI Infective lesions show usually greater uptake of 67 67 99m Ga-citrate Ga in comparison to Tc-HDP/MDP while 4 h p.i. total body, planar and an aseptic process (arthritis, fracture etc) shows 99m SPECT(/CT) images ROI greater uptake of Tc-HDP/MDP than that of 24 h p.i. planar images ROI Ga. 48 h p.i. planar and [ F]FDG PET/CT: SPECT(/CT) images ROI, Infective lesions show greater uptake of if necessary [ F]FDG than healthy vertebral body [ F]FDG PET/CT 1 h p.i. PET/CT Sternal infections Labeled WBC and Qualitative analysis: Medicate the wound before scintigraphic 99m Tc-mAb-anti-granulocy- an increased uptake with time of sternum and/or acquisition to avoid FP results. tes: mediastinum is indicative of infection. FP results: 30 min p.i. Planar images for Semi-quantitative analysis: missed clearing of wound before scintigraphic QC and ROI Pattern I: Presence of deep infection. Widespread acquisition 3–4 h p.i. total-body, planar and intense uptake of the sternum, greater than and SPECT(/CT) images liver uptake, after 3–4and 20–24 h. ROI. Pattern II: Presence of superficial infection. 20–24 h p.i. planar and Moderate increase or irregular uptake of SPECT(/CT) images ROI sternum that does not change or decrease between 3 and 4 and 20–24 h. Pattern III: Absence of infection. Medium intensity uptake with uniform distribution of the sternum, abnormal uptake (Bcold^ areas) on the midline or cold areas with focal distribution in the midline Diabetic foot Labeled WBC and Semi-quantitative analysis: Clean the wound before scintigraphy 99m Tc-mAb-anti-granulocy- Infective lesions show an uptake that rises over acquisition to avoid FP. Assess the presence tes: time while aseptic flogistic lesions show a of lesions of size lower than spatial 30 min p.i. planar images for decreasing uptake over time. In doubtful cases resolution of method QC and ROI it is necessary to compare the images with 99m 3–4 h p.i. total-body and pla- Tc-sulfur colloids infective lesion to check nar images ROI for a mismatch pattern of radiopharmaceuticals 20–24 h p.i. planar and uptake SPECT(/CT) images ROI 99m Tc-sulfur colloids 20–360 min p.i. planar images QC quality control, ROI region of interest uptake at 2–4 h p.i.. Labeled neutrophils accumulate prefer- spleen. During the following hours, labeled cells migrate from entially in the liver and eosinophils preferentially into the spleen and bone morrow to infected tissues. This is the reason 1826 Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 Table 4 Summary of acquisition/interpretation protocols of soft tissues infections Examination Acquisition Image interpretation Pitfalls protocol Central nervous system Labeled WBC: Semi-quantitative analysis: infections 30 min p.i. planar images for Infective lesions show usually an uptake equal to QC and ROI +++/++++ while aseptic lesions show no uptake or equal 3–4 h p.i. total-body and pla- to +/++ nar images ROI 20–24 h p.i. planar and SPECT(/CT) images ROI Infective endocarditis Labeled WBC: Qualitative analysis: Assess the presence of artifacts related to the attenuation overcorrection for the 30 min p.i. planar images for analysis of cardiac region (valve plans) and other regions presence of surgical implants (mechanical valve prostheses and CIED). QC and ROI (CNS, spleen and axial skeleton, lung) FN results: 3–4 h p.i. total-body, planar Anatomic location of WBC uptake. fungal endocarditis and SPECT(/CT) images Correlation with flogosis markers and echocardiography. FP results: ROI atherosclerotic plaques, sarcoidosis, tumor, vasculitis etc 20–24 h p.i. planar and SPECT(/CT) images ROI Clinical history (date and sort of surgical procedure). Assess the presence of artifacts related to the attenuation overcorrection in Post surgical infections (dermal Labeled WBC: filler infections and 30 min p.i. Planar images for Anatomic location of WBC uptake. patients with metallic devices abscesses) QC and ROI Correlation with flogosis markers 3–4 h p.i. total-body, planar and SPECT(/CT) images ROI 20–24 h p.i. planar and SPECT(/CT) images ROI Pulmonary infections Labeled WBC: Focal pulmonary uptake that arise over time is usually FP results: 30 min p.i. Planar images for associated with bacterial pneumonia. cystic fibrosis, faulty labelling or reinjection QC and ROI Diffuse pulmonary activity on images obtained 4 h p.i. can 3–4 h p.i. total-body planar be due to opportunistic infections, radiation pneumonitis, and SPECT(/CT) images pulmonary drug toxicity and adult respiratory distress ROI syndrome 20–24 h p.i. planar and SPECT(/CT) images ROI QC quality control, ROI region of interest Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 1827 Table 5 Summary of acquisition/interpretation protocols of others infections Examination Acquisition Image interpretation Pitfalls protocol 99m Fever of Labeled WBC and Tc-mAb-anti-granulocytes: Evaluation of all regions of increased uptake having regard to Assess the presence of artifacts related to the attenuation unknown 30 min p.i. planar images for QC and ROI the overcorrection in patients with metallic devices or prostheses origin 3–4 h p.i. total-body and planar images ROI possible differential diagnosis (inflammation, cancer) 20–24 h p.i. planar and SPECT(/CT) images ROI 99m Inflammatory Labeled WBC and Tc-mAb-anti-granulocytes: Abscesses and fistulae can appear only at late images. Better Starting from 3 h p.i. due to aspecific accumulation of secondary bowel 30 min-1 h p.i. planar images for QC and ROI to hydrophilic complexes of Tc in caecum and ascending colon diseases 2–2.5 h p.i. planar and SPECT(/CT) images ROI use SPECT/CT in case of doubt. after 2 h p.i. planar image of the chest (in patients with suspected FP results can be obtained in tumor. Aspecific uptake in oesophageal localization of disease). colitis, bleeding and diabetic patients 99m 24 h p.i. planar images ROI for Tc mAb or for abscesses and fistulae 99m Vascular Labeled WBC and Tc-mAb-anti-granulocytes: Clinical history (date and sort of vascular prosthesis implant, Assess the presence of artifacts related to the attenuation prosthesis i.v. injection during dynamic acquisition (one image every etc). overcorrection in patients with metallic clips. 5–10 s for 3–5min) Anatomic location of WBC uptake (in vascular prosthesis FN results: 30 min p.i. planar images for QC and ROI wall, chronic flogistic process with low recruitment 3–4 h p.i. total-body, planar and SPECT(/CT) images ROI at the site of surgical clips and/or in soft tissues) of WBC 20–24 h p.i. recommended if the chest is the ROI QC quality control, ROI region of interest 1828 Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 why bone marrow activity decreases with time and infection antibodies, the uptake of liver > spleen, and very intense up- shows an increase of activity with time. Although pulmonary take is seen in the kidneys due to predominantly renal excre- 99m uptake of labeled WBCs is physiologic during the first few tion of Tc-anti-NCA-90 (Fab’) and non-specific bowel ac- hours after injection, at 4 and 24 h p.i. such lung activity is tivity is already seen 4–6 h p.i. due to enzymatic liver degra- abnormal. Focal segmental or lobar pulmonary uptake is also dation of the compound. associated as a rule with infection. Non-segmental focal pul- Monoclonal antibodies allow rapid and safe delineation of monary uptake in early images, however, is usually caused by inflammatory foci by efficient accumulation on the surface of technical problems during labelling or reinfusion and is gen- chemotactic activated granulocytes. The decrease of molecu- erally not associated with infection. lar size increases the background clearance together with a Cell migration is largely influenced by the vascularization significant reduction of non-specific accumulation in other on the infected region. In spondylodiscitis there a reduced organs hampering image interpretation. Antibodies bind to blood flow due to oedema that compresses small capillaries granulocytes with high affinity (with K in the nanomolar and makes it difficult for granulocytes to accumulate in the range) being specifically involved in the process of infection region. Similarly, in diabetic foot infection a poor vasculature without undesirable expression of targets in non-infected of distal toes has been described, thus migration of leukocytes tissues. can be impaired in soft tissue infections but still present when Furthermore, it is generally accepted that anti-G-mAbs lo- bone is infected. This different trend between soft tissue in- calize in infectious foci by two pathways: (a) in-vivo targeting fection and osteomyelitis has been reported only for diabetic of chemotactically activated granulocytes and (b) non-specific foot infections and can allow differentiation of soft tissue in- extravasation due to the locally enhanced vascular permeabil- fections from osteomyelitis but not soft tissue infections from ity, the later allowing delayed targeting at 10–20% ID. sterile inflammation [14]. Monoclonal antibodies visualize infectious foci in patients In-labeled WBC do not accumulate in the normal bowel. with a sensitivity between 80 and 90%, are very useful in the Intestinal activity is always abnormal and should be seen in evaluation of bone prosthetic infections (and in this case a com- antibiotic-associated colitis, pseudomembranous colitis, infec- bination with 3-phase bone scan is highly recommended) as well tious colitis, IBD, ischemic colitis or gastrointestinal bleeding. as of soft tissue infections such as vascular graft infection, pros- WBC do not usually accumulate in healing surgical thetic heart valve infection and inflammatory bowel disease wounds and their presence in these sites indicates a soft- [80–83], although these agents appear to be somewhat less accu- tissue infection. When the wound is very close to the bone rate than labeled leukocytes. Pulmonary infections—with the ex- surface (as in feet, tibia, skull, etc.) it might be difficult to ceptionoflungabscesses—are not easily visualized. Peripheral discriminate between soft tissue involvement alone or bone bone infections can be adequately visualized, but the sensitivity involvement too. Since OM is always much more clinically decreases if the focus is located closer to the spine [84]. relevant than a soft tissue infection, a differential diagnosis The major disadvantages of the murine monoclonal anti- must be made and SPECT/CT acquisitions may help in this bodies are that they are registered in Europe only for osteo- evaluation. myelitis diagnosis and that they may induce formation of hu- There are, however, certain exceptions to the rule. man anti-mouse antibodies (HAMA), which can result in al- Granulating wounds that heal by secondary intention can ap- tered biodistribution of subsequent injections [84]. pear as areas of intense uptake on WBC images even in the Colorimetric kit tests for rapid measurements of HAMA, how- absence of infection. Examples include stomas (e.g. tracheos- ever, are now commercially available and very easy to use tomy, ileostomy, feeding gastrostomy, etc.) and skin grafts. giving a result in less than 5 min. Vascular access lines, dialysis catheters and even lumbar punctures can all produce false-positive results and therefore Report of scintigraphic findings the importance of knowledge of the clinical history. A possible cause of non-infective accumulation of WBC in The final report of the study should be divided into five parts: the bone is the Paget disease. identification, clinical question, procedure description, report With complete and fragmented mAbs some differences in text and conclusions. physiological uptake should always be taken into consider- 99m ation: complete Tc-anti-NCA-95 antibody scans show in- & Identification: this includes the patient identification, the tense uptake in bone marrow, spleen > liver already 1–4 h p.i., institution where the scintigraphy was performed, the date whereas both kidneys are shown only slightly. Non-specific of scintigraphy, the type of scintigraphy, the name of ra- bowel activity is regularly seen after 20–24 h p.i. due to the diopharmaceutical and the activity administered to patient beginning of radiolabel instability. (MBq), and any other specification required by national 99m With Tc-anti-NCA-90 (Fab’) antibodies, bone marrow regulations, e.g. the name of the radiographer performing the study. is shown in a much lower degree as compared with complete Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 1829 Open Access This article is distributed under the terms of the Creative & Clinical question: this includes the clinical question and Commons Attribution 4.0 International License (http:// brief clinical history of the patient. Current treatment with creativecommons.org/licenses/by/4.0/), which permits unrestricted use, antibiotics or other interfering drugs should be reported. distribution, and reproduction in any medium, provided you give appro- & Procedure description: this includes the description of priate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. instrumentation used, the administration method of the radiopharmaceutical and the acquisition protocol. The use of SOPs should be mentioned as well as the European Guidelines for labelling, image acquisition and interpretation. References & Report text: this includes the description of qualitative and/ or semi-quantitative analysis. The qualitative analysis should 1. Signore A, Quintero AM. Diagnostic imaging of infections and inflammatory diseases: a multi-disciplinary approach. New York: describe the presence/absence of radiopharmaceutical Wiley; 2013. uptake, the site and size of uptake, and the intensity of up- 2. Lazzeri E, Signore A, Erba PA, Prandini N, Versari A, D’Errico G, take, preferably supported by semi-quantitative data. The et al. Radionuclide imaging of infection and inflammation. A pic- possible presence of factors that may have limited the sensi- torial case-based atlas. Italia: Springer-Verlag; 2013. tivity and specificity of the study, such as the presence of 3. Annovazzi A, Bagni B, Burroni L, D’Alessandria C, Signore A. Nuclear medicine imaging of inflammatory/infective disorders of motion artifacts, should be described. the abdomen. Nucl Med Commun. 2005;26:657–64. & Conclusions: This is the clear and conclusive answer to 4. Prandini N, Lazzeri E, Rossi B, Erba P, Parisella MG, Signore A. the clinical question. It can also suggest other diagnostic Nuclear medicine imaging of bone infections. Nucl Med Commun. procedures to be performed to confirm or exclude the di- 2006;27:633–44. agnosis made. The anatomical structures involved, as well 5. Cascini GL, De Palma D, Matteucci F, Biggi A, Rambaldi PF, Signore A, et al. Fever of unknown origin, infection of subcutane- as the presence, extent and the intensity of the infectious ous devices, brain abscesses and endocarditis. Nucl Med Commun. process have to be specified. At the end of the conclusions 2006;27:213–22. the name and surname of the Nuclear Medicine Physician 6. Capriotti G, Chianelli M, Signore A. Nuclear medicine imaging of reporting the study and of the technician performing the diabetic foot infection: results of meta-analysis. Nucl Med Commun. 2006;27:757–64. scan have to be clearly stated. 7. de Vries EF, Roca M, Jamar F, Israel O, Signore A. Guidelines for the labelling of leucocytes with (99m)Tc-HMPAO. Inflammation/ Acknowledgments The EANM Committee on Infection/Inflammation infection Taskgroup of the European Association of Nuclear Imaging would like to thank the following colleagues: Riddhika Medicine. Eur J Nucl Med Mol Imaging. 2010;37(4):842–8. Chakravartty, Paola Erba, Andor Glaudemans, Chiara Lauri, Olivier (Erratum in: Eur J Nucl Med Mol Imaging. 2010; 37(6):1235) Gheysens, Stephan Gratz, Napoleone Prandini and Francois Rouzet, 8. Roca M, de Vries EF, Jamar F, Israel O, Signore A. Guidelines for and for useful discussion and contribution to these guidelines. the labelling of leucocytes with (111)in-oxine. Inflammation/ The guidelines were brought to the attention of all other EANM infection Taskgroup of the European Association of Nuclear Committees and to the National Societies of Nuclear Medicine. The com- Medicine. Eur J Nucl Med Mol Imaging. 2010;37(4):835–41. ments and suggestions from the Pediatric, Oncology, Radiopharmacy and (Erratum in: Eur J Nucl Med Mol Imaging. 2010; 37(6):1234) the Physics Committee and from the Belgian, Italian and Finnish National 9. Signore A, Glaudemans AWJM, Malviya G, Lazzeri E, Prandini N, Societies are highly appreciated and have been considered for this Viglietti AL, et al. Development and testing of a new disposable Guideline. The publication of this article was supported by funds of the sterile device for labelling white blood cells. Q J Nucl Med Mol European Association of Nuclear Medicine (EANM). Imaging. 2012;56(4):400–8. 10. Locher JT, Seybold K, Andres RJ, Schubiger PA, Mach JP, Compliance with ethical standards Buchegger F. Imaging of inflammatory and infectious lesions after injection of radioiodinated monoclonal antigranulocyte antibodies. Disclaimer The European Association of Nuclear Medicine (EANM) Nucl Med Commun. 1986;7:659–70. has written and approved guidelines to promote the use of nuclear med- 11. Becker W, Bair J, Behr T, Repp R, Streckenbach H, Beck H, et al. icine procedures of high quality. The guidelines should not be deemed Detection of soft-tissue infections and osteomyelitis using a inclusive of all proper procedures and exclusive of other procedures rea- technetium-99m-labeled anti-granulocyte monoclonal antibody sonably directed to obtaining the same results. fragment. J Nucl Med. 1994;35(9):1436–43. The facilities in a specialized practice setting may be different from 12. Gratz S, Reize P, Kemke B, Kampen WU, Lusteri M, Hoffken H. those in a more general setting. Resources available to care for patients, Targeting of osteomyelitis with IgG and Fab’ monoclonal antibod- legislation and local regulations may vary greatly from one European ies labeled with [99mTc]: kinetic evaluations. Q J Nucl Med Mol country or one medical facility to another. For these reasons, these guide- Imaging. 2014;60:413–23. lines cannot be rigidly applied. 13. Palestro CJ, Mehta HH, Patel M, Freeman SJ, Harrington WN, Tomas MB, et al. Marrow versus infection in the Charcot joint: Conflict of interest All authors declare that they have no conflict of indium-111 leukocyte and technetium-99msulfur colloid scintigra- interest. phy. J Nucl Med. 1998;39:346–50. 14. Familiari D, Glaudemans AW, Vitale V, Prosperi D, Bagni O, Lenza Ethical approval This article does not contain any studies with human A, et al. Can sequential 18F-FDG PET/CT replace WBC imaging in participants or animals performed by any of the authors. the diabetic foot? J Nucl Med. 2011;52(7):1012–9. 1830 Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 15. Israel O, Sconfienza LM, Lipsky BA. Diagnosing diabetic foot 31. Panes J, Bouhnik Y, Reinisch W, Stoker J, Taylor SA, Baumgart DC, et al. Imaging techniques for assessment of inflammatory bow- infection: the role of imaging and a proposed flow chart for assess- ment. Q J Nucl Med Mol Imaging. 2014;58:33–45. el disease: joint ECCO and ESGAR evidence-based consensus guidelines. J Crohn’s Colitis. 2013;7(7):556–85. 16. Palestro CJ, Love C. Radionuclide imaging of musculoskeletal in- 32. Martín Comín J, Rodríguez Gasén A, Van de Wiele C. Nuclear fection: conventional agents. Semin Musculoskelet Radiol. medicine imaging of infections and inflammatory diseases of the 2007;11:335–52. abdomen. In: Signore A, Quintero AM, editors. Diagnostic imaging 17. Sonmezoglu K, Sonmezoglu M, Halac M, Akgün I, Türkmen C, of infections and inflammatory diseases: a multi-disciplinary ap- Onsel C, et al. Usefulness of 99mTc-ciprofloxacin (infecton) scan in proach. New York: Wiley; 2013. p. 216–40. diagnosis of chronic orthopedic infections: comparative study with 33. Signore A. Nuclear medicine imaging of abdominal infections and 99mTc-HMPAO leukocyte scintigraphy. J Nucl Med. 2001;42(4): inflammation. In: Lazzeri E, Signore A, Erba PA, Prandini N, 567–74. Versari A, D’Errico G, Mariani G, editors. Radionuclide imaging 18. Palestro CJ, Love C, Tronco GG, Tomas MB, Rini JN. Combined of infection and inflammation. A pictorial case-based atlas. Italia: labeled leukocyte and technetium-99m sulfur colloid marrow im- Springer-Verlag; 2013. p. 229–52. aging for diagnosing musculoskeletal infection: principles, tech- 34. Durack DT. Fever of unknown origin. In: Mackoviac PA, editor. nique, interpretation, indications and limitations. Radiographics. Fever. Basic mechanisms and management. 2nd ed. Philadelphia: 2006;26:859–70. Lippincott-Raven Pbl; 1997. p. 237–49. 19. Ballani NS, Al-Huda FA, Khan HA, Al-Mohannadi S, Mahmood H, 35. Peters AM. Nuclear medicine imaging in fever of unknown origin. Al-Enezi F. The value of quantitative uptake of (99m)Tc-MDP and Q J Nucl Med. 1999;43(1):61–73. (99m)Tc-HMPAO white blood cells in detecting osteomyelitis in vio- 36. Mourad O, Palda V, Detsky AS. A comprehensive evidence-based lated peripheral bones. J Nucl Med Technol. 2007;35(2):91–5. approach to fever of unknown origin. Arch Intern Med. 20. Jutte P, Lazzeri E, Sconfienza LM, Cassar-Pullicino V, Trampuz A, 2003;163(5):545–51. Petrosillo N, et al. Diagnostic flowcharts in osteomyelitis, 37. Xavier Hanin F, Jamar F. Nuclear medicine imaging of fever of spondylodiscitis and prosthetic joint infection. Q J Nucl Med Mol unknown origin. In: Signore A, Quintero AM, editors. Diagnostic Imaging. 2014;58:2–19. imaging of infections and inflammatory diseases: a multi- 21. van der Bruggen W, Bleeker-Rovers CP, Boerman OC, Gotthardt disciplinary approach. New York: Wiley; 2013. p. 273–90. M, Oyen WJG. PET and SPECT in osteomyelitis and prosthetic 38. Seshadri N, Solanki CK, Balan K. Utility of 111In-labeelled leuko- bone and joint infections: a systematic review. Semin Nucl Med. cyte scintigraphy in patients with fever of unknown origin in an era 2010;40:3–15. of changing disease spectrum and investigational techniques. Nucl 22. Palestro CJ. Nuclear medicine imaging of osteomyelitis: white Med Commun. 2008;29:277–82. blood cell, monoclonal antibody, or bacterial imaging? In: 39. Ascher NL, Ahrenholz DH, Simmons RL, Weiblen B, Gomez L, Signore A, Quintero AM, editors. Diagnostic imaging of infections Forstrom LA, et al. Indium-111 autologous tagged leukocytes in the and inflammatory diseases: a multi-disciplinary approach. New diagnosis of intraperitoneal sepsis. Arch Surg. 1979;114:386–92. York: Wiley; 2013. p. 168–86. 40. Coleman RE, Black RE, Welch OM, Maxwell JG. Indium-ill la- 23. Lazzeri E, Erba PA, Sollini M, Mariani G. Nuclear medicine imag- beled leukocytes in the evaluation of suspected abdominal abscess- ing of spondylodiscitis: the emerging role of PET. In: Signore A, es. Am J Surg. 1980;139:99–104. Quintero AM, editors. Diagnostic imaging of infections and inflam- 41. Morales KB. Nuclear medicine imaging of soft tissue infections. In: matory diseases: a multi-disciplinary approach. New York: Wiley; Signore A, Quintero AM, editors. Diagnostic imaging of infections 2013. p. 187–98. and inflammatory diseases: a multi-disciplinary approach. New 24. Fuster D, Tomás X, Mayoral M, Soriano A, Manchón F, Cardenal York: Wiley; 2013. p. 199–215. C, et al. Prospective comparison of whole-body (18)F-FDG PET/ 42. Palestro CJ. Love C, TroncoGG, Tomas MB. Role of radionuclide CT and MRI of the spine in the diagnosis of haematogenous imaging in the diagnosis of postoperative infection. Radiographics. spondylodiscitis. Eur J Nucl Med Mol Imaging. 2015;42(2):264– 2000;20:1649–60. 43. Borst U, Becker W, Maisch B, Börner W, Kochsiek K. Indium-111 25. Hungenbach S, Delank KS, Dietlein M, Eysel P, Drzezga A, or Tc-99m-HMPAO marked granulocytes as specific markers of Schmidt MC. 18F-fluorodeoxyglucose uptake pattern in patients florid stage endocarditis–results comparing clinical, histological with suspected spondylodiscitis. Nucl Med Commun. and scintigraphic findings in 30 patients with suspected endocardi- 2013;34(11):1068–74. tis. Z Kardiol. 1992;81(8):432–7. 26. Jamar F, Buscombe J, Chiti A, Christian PE, Delbeke D, Donohoe 44. Campeau RJ, Ingram C. Perivalvular abscess complicating infec- KJ, et al. EANM/SNMMI guideline for 18F-FDG use in inflamma- tive endocarditis: complementary role of echocardiography and tion and infection. J Nucl Med. 2013;54(4):647–58. indium-111-labeled leukocytes. ClinNucl Med. 1998;23(9):582–4. 27. Mulamba L, Ferrant A, Leners N, de Nayer P, Rombouts JJ, Vincent 45. Morguet AJ, Munz DL, Ivancević V, Werner GS, Sandrock D, A. Indium-111 leucocyte scanning in the evaluation of painful hip Bökemeier M, et al. Immunoscintigraphy using technetium-99m- arthroplasty. Acta Orthop Scand. 1983;54(5):695–7. labeled anti-NCA-95 antigranulocyte antibodies as an adjunct to 28. Palestro CJ, Kim CK, Swyer AJ, Capozzi JD, Solomon RW, echocardiography in subacute infective endocarditis. J Am Coll Goldsmith SJ. Total hip arthroplasty: periprosthetic In labeled Cardiol. 1994;23(5):1171–8. 99m leukocyte activity and complementary Tc sulfur colloid imaging 46. Erba P, Conti U, Lazzeri E, Sollini M, Doria R, De Tommasi SM, et 99m in suspected infection. J Nucl Med. 1990;31:1950–5. al. Added value of Tc-HMPAO labelled leukocytes SPECT/CT 29. Palestro CJ, Swyer AJ, Kim CK, Goldsmith SJ. Infected knee pros- imaging in the characterization and management of patient with thesis: diagnosis with in-111-leukocyte, Tc-99m-sulfur colloid and infectious endocarditis. J Nucl Med. 2012;53(8):1235–43. Tc-99m-MDP imaging. Radiology. 1991;179:645–8. 47. Iung B, Erba PA, Petrosillo N, Lazzeri E. Common diagnostic 30. Love C, Marwin SE, Tomas MB, Krauss ES, Tronco GG, Bhargava flowcharts in infective endocarditis. Q J Nucl Med Mol Imaging. KK, et al. Diagnosing infection in the failed joint replacement: a 2014;58:55–65. comparison of coincidence detection fluorine-18 FDG and indium- 48. Fiorani P, Speziale F, Rizzo L, De Santis F, Massimi GJ, Taurino M, 111-labelled leukocyte/technetium-99m-sulfur colloid marrow im- et al. Detection of aortic graft infection with leukocytes labeled with aging. J Nucl Med. 2004;45:1864–71. technetium 99m-hexametazime. J Vasc Surg. 1993;17:87–96. Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 1831 49. Krznaric E, Nevelsteen A, Van Hoe L, de Roo M, Schiepers C, 67. Sampson CB. Complications and difficulties in radiolabelling 99 m blood cells: a review. Nucl Med Commun. 1996;17(8):648–58. Verbuggen A, et al. Diagnostic value of Tc -d,l-HMPAO-labelled leukocyte scintigraphy in the detection of vascular graft infections. 68. Sampson CB. Interference of patient medication in the Nucl Med Commun. 1994;15:953–60. radiolabelling of white blood cells: un update. Nucl Med 50. Prats E, Banzo J, Abós MD, Garcia-Lopex F, Escalera T, Garcia- Commun. 1998;19(6):529–33. Miralles M, et al. Diagnosis of prosthetic vascular graft infection by 69. Glaudemans AW, de Vries EF, Vermeulen LE, Slart RH, Dierckx technetium-99m-HMPAO-labeled leukocytes. J Nucl Med. RA, Signore A. A large retrospective single-Centre study to define 1994;35:1303–7. the best image acquisition protocols and interpretation criteria for 99m 51. Liberatore M, Iurilli AP, Ponzo F, Prosperi D, Santini C, Baiocchi P, white blood cell scintigraphy with Tc-HMPAO-labelled et al. Aortofemoral graft infection: the usefulness of 99m-Tc- leucocytes in musculoskeletal infections. Eur J Nucl Med Mol HMPAO-labelled leukocyte scan. Eur J VascEndovasc Surg. Imaging. 2013;40(11):1760–9. 1997;14(Suppl A):27–9. 70. Erba PA, Glaudemans AW, Veltman NC, Sollini M, Pacilio M, Galli 52. Setacci C, Müller-Hülsbeck S, Jamar F. Common diagnostic flow- F, et al. Image acquisition and interpretation criteria for (99m)Tc- charts in vascular and endovascular surgery. Q J Nucl Med Mol HMPAO-labelled white blood cell scintigraphy: results of a Imaging. 2014;58:46–54. multicentre study. Eur J Nucl Med Mol Imaging. 2014;41(4):615–23. 53. Israel O. Nuclear medicine imaging of vascular graft infection: the 71. Grippaudo FR, Pacilio M, Di Girolamo M, Dierckx RA, Signore A. added role of hybrid imaging. In: Signore A, Quintero AM, editors. Radiolabelled white blood cell scintigraphy in the work-up of der- Diagnostic imaging of infections and inflammatory diseases: a mal filler complications. Eur J Nucl Med Mol Imaging. 2013;40(3): multi-disciplinary approach. New York: Wiley; 2013. p. 241–54. 418–25. 54. Love C, Opoku-Agyemang P, Tomas MB, Pugliese PV, Bhargava 72. Rubello D, Casara D, Maran A, Avogaro A, Tiengo A, Muzzio PC. KK, Palestro CJ. Pulmonary activity on labeled leukocyte images: Role of anti-granulocyte Fab’ fragment antibody scintigraphy physiologic, pathologic, and imaging correlations. Radiographics. (LeukoScan) in evaluating bone infection: acquisition protocol, in- 2002;22:1385–93. terpretation criteria and clinical results. Nucl Med Commun. 55. Palestro C, Swyer AJ, Kim CK, Muzinic M, Goldsmith SJ. Role of 2004;25(1):39–47. 111In-labeled leukocyte scintigraphy in the diagnosis of intracere- 73. Rubello D, Rampin L, Banti E, Massaro A, Cittadin S, Cattelan bral lesions. Clin Nucl Med. 1991;16:305–8. AM, et al. Diagnosis of infected total knee arthroplasty with anti- 56. Kim DG, Lee JL, Lee DS, Lee MC, Choi KS, Han DH. 99mTc- granulocyte scintigraphy: the importance of a dual-time acquisition HMPAO labeled leukocyte SPECT in intracranial lesions. Surg protocol. Nucl Med Commun. 2008;29(4):331–5. Neurol. 1995;44:338–45. 74. Skehan SJ, White JF, Evans JW, Parry-Jones DR, Solanki CK, 99m 57. Grimstad IA, Hirschberg H, Rootwelt K. 99mTc- Ballinger JR, et al. Mechanism of accumulation of Tc- hexamethylpropylene amine oxime leucocyte scintigraphy and sulesomab in inflammation. J Nucl Med. 2003;44(1):11–8. C-reactive protein levels in the differential diagnosis of brain ab- 75. Peters AM, Ballinger JR. Timing for evaluating Bspecific^ binding 99m scesses. J Neurosurg. 1992;77:732–6. of Tc-sulesomab in peripheral bone infection. J Nucl Med. 58. Spinelli F, Sara R, Milella M, Ruffini L, Sterzi R, Causarano IR, et 2005;46(2):382–3. al. Technetium-99m hexamethylpropylene amine oxime leucocyte 76. Pelosi E, Baiocco C, Pennone M, Migliaretti G, Varetto T, Maiello scintigraphy in the differential diagnosis of cerebral abscesses. Eur J A, et al. 99mTc-HMPAO-leukocyte scintigraphy in patients with Nucl Med. 2000;27:46–9. symptomatic total hip or knee arthroplasty: improved diagnostic 59. Medina M, Viglietti AL, Gozzoli L, Lucano A, Ravasi L, Lucignani accuracy by means of semiquantitative evaluation. J Nucl Med. G, et al. Indium-111 labelled white blood cell scintigraphy in cranial 2004;45(3):438–44. and spinal septic lesions. Eur J Nucl Med. 2000;27:1473–80. 77. Wang SJ, Kao CH, Chen DU, Lin MS, Yeh SH, Lan JL. 60. Goethals I, Dierckx R, Van Laere K, Van de Wiele C, Signore A. Quantitative 99mTc-HMPAO white blood cells and 67Ga scanning The role of nuclear medicine imaging in routine assesment of in- in rheumatoid arthritis. Nucl Med Commun. 1991;12(6):551–8. fections brain pathology. Nucl Med Commun. 2002;23:819–26. 78. MacSweeney JE, Peters AM, Lavender JP. Indium labelled leuco- 61. Signore A, Biggi A. Nuclear medicine imaging of infections and cyte scanning in pyrexia of unknown origin. ClinRadiol. 1990 inflammation of central nervous system, head and neck structures. Dec;42(6):414–7. 99m In: Lazzeri E, Sigmore A, Erba PA, Prandini N, Versari A, D’Errico 79. Gutfilen B, Lopes de Souza SA, Martins FP, et al. Use of Tc- G, Mariani G, editors. Radionuclide imaging of infection and in- mononuclear leukocyte scintigraphy in nosocomial fever. Acta flammation. Italia: Springer-Verlag; 2013. p. 165–80. Radiol. 2006;47(7):699–704. 62. Sandrock D, Verheggen R, Helwig AT, Munz DL, Makakis E, 80. Becker W, Bair J, Behr T, et al. Detection of soft-tissue infections Emrich D. Immunoscintigraphy in the detection of brain abscesses. and osteomyelitis using a technetium-99m labelled anti granulocyte Nucl Med Commun. 1996;17:311–6. monoclonal antibody fragment. J Nucl Med. 1994;35:1436–43. 63. Schmidt KG, Rasmussen JW, Frederiksen PB, Kock-Jensen C, 81. Gratz S, Schipper ML, Dörner J, et al. LeukoScan for imaging Pedersen NT. Indium-ill-granulocyte scintigraphy in brain abscess infection in different clinical settings: a retrospective evaluation diagnosis: limitations and pitfalls. J Nucl Med. 1990;31:1121–7. and extended review of the literature. Clin Nucl Med. 2003;4: 64. Fineman D, Palestro CJ, Kim CK, Needle LB, Vallabhajosula S, 267–76. Solomon RW, et al. Detection of abnormalities in febrile AIDS 82. Papos M, Nagy F, Narai G,etal. Anti-granulocyte patients with In-111-labeled leukocyte and GA-67 scintigraphy. immunoscintigraphy and [99mTc]hexamethylpropyleneamine-ox- Radiology. 1989;170:677–80. ime-labeled leukocyte scintigraphy in inflammatory bowel disease. 65. Palestro CJ, Goldsmith SJ. The use of gallium and labeled leuko- Dig Dis Sci. 1996;41:412–20. cyte scintigraphy in the AIDS patient. Q J Nucl Med. 1995;39:221– 83. Gratz S, Braun HG, Behr TM, et al. Photopenia in chronic vertebral 30. osteomyelitis with technetium - 99mTc-antigranulocyte antibody 66. Sathekge M, Van de Wiele C, Signore A. Nuclear medicine imaging (BW 250/183). J Nucl Med. 1997;38(2):211–6. of tuberculosis and human immunodeficiency virus. In: Signore A, 84. Meller J, Liersch T, Oezerden MM, Sahlmann C-O, Meller B. Quintero AM, editors. Diagnostic imaging of infections and inflam- Targeting NCA-95 and other granulocytes antigen and receptors matory diseases: a multi-disciplinary approach. New York: Wiley; with radiolabeled monoclonal antibodies (Mabs). Q J Nucl Med 2013. p. 255–72. Mol Imaging. 2010;54:582–98. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Nuclear Medicine and Molecular Imaging Springer Journals

Clinical indications, image acquisition and data interpretation for white blood cells and anti-granulocyte monoclonal antibody scintigraphy: an EANM procedural guideline

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Medicine & Public Health; Nuclear Medicine; Imaging / Radiology; Orthopedics; Cardiology; Oncology
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Abstract

Introduction Radiolabelled autologous white blood cells (WBC) scintigraphy is being standardized all over the world to ensure high quality, specificity and reproducibility. Similarly, in many European countries radiolabelled anti-granulocyte antibodies (anti-G-mAb) are used instead of WBC with high diagnostic accuracy. The EANM Inflammation & Infection Committee is deeply involved in this process of standardization as a primary goal of the group. Aim The main aim of this guideline is to support and promote good clinical practice despite the complex environment of a national health care system with its ethical, economic and legal aspects that must also be taken into consideration. Method After the standardization of the WBC labelling procedure (already published), a group of experts from the EANM Infection & Inflammation Committee developed and validated these guidelines based on published evidences. Results Here we describe image acquisition protocols, image display procedures and image analyses as well as image interpre- tation criteria for the use of radiolabelled WBC and monoclonal antigranulocyte antibodies. Clinical application for WBC and anti-G-mAb scintigraphy is also described. Conclusions These guidelines should be applied by all nuclear medicine centers in favor of a highly reproducible standardized practice. . . . . Keywords Infection Inflammation Acquisition protocols WBC Monoclonal antibodies Introduction way images should be acquired and interpreted. It is not the aim of this guideline to compare the indication of different Scintigraphy using radiolabelled white blood cells (WBC) and nuclear medicine modalities and radiopharmaceuticals in clin- anti-granulocyte monoclonal antibodies (anti-G mAb) has ical practice. Several reviews are available for advanced and been used in a variety of different clinical situations [1, 2]. more comprehensive readings on the topic, including four While it is difficult to draw evidence-based statistical conclu- papers which have been recently published with meta- sions for some clinical applications, for other infectious pro- analysis of data collected between 1985 and 2005 on the clin- cesses the role of these imaging tools is well standardized, ical use of radiolabelled WBC as compared to other available with grade A or B levels of evidence. diagnostic techniques [3–6]. Here we summarize the most important clinical indications The main aim of these guidelines is to support and promote in which WBC or anti-granulocyte mAbs can be used and the good clinical practice. Nevertheless, guidelines are used in the * A. Signore Department of Nuclear Medicine, Rambam Health Care Campus, alberto.signore@uniroma1.it Haifa, Israel Department of Nuclear Medicine, Cambridge Biomedical Campus, Cambridge, UK Nuclear Medicine Unit, Department of Medical-Surgical Sciences and Translational Medicine, BSapienza^ University of Rome, Nuclear Medicine Department, Hospital Universitario de Bellvitge, Ospedale S. Andrea, Via di Grottarossa 1035, 00189 Rome, Italy Barcelona, Spain Department of Nuclear Medicine, Université Catholique de Louvain, Regional Center of Nuclear Medicine, Azienda Brussels, Belgium Ospedaliero-Universitaria Pisana, Pisa, Italy Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 1817 complex environment of a health care system with its ethical, plasma, and images at 20–24 h after injection are more economic, legal and other aspects that need to be taken into reliable than if using Sulesomab. Furthermore, consideration in each country. Besilesomab, being a murine antibody may induce produc- tion of human anti-mouse antibodies (HAMA) that must be Autologous WBC and anti-G-mAbs checked before performing the study and limit its use to one single administration in life. Sulesomab, being a Fab’ Autologous white blood cells (mainly neutrophils) can be fragment, does not induce HAMA production and can be 99m 111 radiolabelled ex-vivo using Tc-HMPAO or In-oxine re-used several times in the same patient, but it is licensed as described elsewhere [7, 8] using sterile conditions in in Europe only for peripheral musculoskeletal infections. accordance with national regulation on the production of medicines. The recent availability of disposable sterile Osteomyelitis and spondylodiscitis closed devices for WBC labelling (Leukokit® and WBC Marker kit®) [9], functioning as disposable mini-isola- Osteomyelitis (OM) is an infection of the bone and bone mar- tors, has enormously facilitated the labelling procedure row due to the presence of aerobic or anaerobic micro-organ- that, however, remains time consuming and requires with- isms, viruses and/or fungi. OM can represent a complication drawing 30–40 ml of blood from patient. Once injected of a systemic infection or can be an infectious process located i.v. in the patient, radiolabelled WBC migrate rapidly to primarily in the bone or surrounding tissue. Of particular clin- the lungs and, if not damaged, proceed to liver, spleen and ical relevance is the differential diagnosis between OM and the reticulo-endothelial system, including bone marrow. soft tissue infection in diabetic patients with Charcot foot or Approximately 1 h after injection, labeled cells further forefoot infections [13–15]. migrate to bone marrow and, in case of an infection, to The most frequent origin of primary OM is haematogenic but the infected tissue due to chemotactic attraction caused by the micro-organisms can also reach the site of infection directly biofilm and its soluble products. The rate of accumulation (in patients with exposed fractures or following surgical proce- of labeled cells in infection sites depends on the site of dures, as in sternal infections) or simply per continuitatem.The infection (cardio-vascular tissue may accumulate WBC haematogenic OM is often caused by gram positive micro-or- within a few hours and much more rapidly than peripheral ganisms, whereas fungi and mycobacteria frequently produce bones and CNS), on the virulence and extent of infection direct and chronic infections. The conditions that predispose to (some bacteria produce more chemotactic factors than primary OM include immunosuppression, previous radiothera- others and some chronic infections or abscesses may py, diabetes mellitus (diabetic foot), drug addiction and hema- show minimal accumulation of leukocytes at late time tological chronic disorders (e.g. sickle-cell anemia). Secondary points), on the type of pathogen (fungal infection may OM is most often associated with (open) trauma, surgery and attract less WBC than bacterial infections), on the as- especially prosthetic implants (see separate paragraph). sumption of antibiotic or steroid therapy (that may reduce OM can be classified as acute, subacute and chronic ac- bacterial virulence or leukocyte migration) and on the cording to the type of onset and clinical course. Patients with status of vascularization of the infected tissue (capillaries acute OM usually present with fever, leukocytosis, elevated in the vertebral body may be compressed by oedema in acute phase reactants (ESR and CRP) and mild or intense pain case of spondylitis thus preventing WBC accumulation as in the affected region. Redness, pain, swelling and impaired well as capillaries in diabetic patients with micro-macro function (the classic rubor, tumor, dolor, calor, function laesa angiopathy/neuropathy or in patients with severe athero- as described by Galen) may also be present. sclerotic lesions). The diagnosis of OM can be challenging. Radiological With the aim of simplifying the procedure of WBC la- techniques, such as computed tomography (CT) and magnetic belling, some anti-granulocyte monoclonal antibodies have resonance imaging (MRI) play an important role, been described. Two products are commercially available: complemented by radionuclide imaging procedures (mainly a whole murine IgG anti-NCA-95 antibody (Besilesomab, radiolabelled white blood cells with nanocolloid scan for bone Scintimun®) [10], and a Fab’ fragment anti-NCA-90 marrow imaging, but also anti-G-mAb scintigraphy) with an (Sulesomab, Leukoscan®) [11]. Both radiopharmaceuti- overall accuracy that exceeds 90% [12, 16–22]. cals bind to peripheral neutrophils but with substantial Radiolabelled WBC is not a valid radiopharmaceutical for biodistribution differences [12]. Besilesomab accumulates the diagnosis of vertebral infections, the frequent lack of up- more than Sulesomab in normal bone marrow, but binds take in the site of infection, as well as in other benign spine more efficiently to neutrophils in blood and at sites of pathology, does not allow for accurate diagnosis or useful infection. It has lower plasma disappearance than follow-up. [ F]FDG PET/CT in association with MRI pro- Sulesomab, thus mimicking the biodistribution of vides the highest diagnostic accuracy [23–26]. Nevertheless, radiolabelled autologous WBC. It is also more stable in in early spondylodiscitis (within 1 week from onset of 1818 Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 symptoms) and in para-vertebral soft tissue infections associ- extramural complications such as abscesses, fistula and perfo- ated with spondylodiscitis, WBC scan can be used. rations [31]. These techniques therefore usually are the first Clinical indications for nuclear medicine evaluation: choice imaging methods due to their availability and good accuracy. WBC scintigraphy allows additional information Peripheral bone osteomyelitis (OM) to be obtained regarding the degree of activity of disease and Suspected OM its extent [31, 32]. There are some limitations to labeled WBC Evaluation of extent of OM imaging in IBD. The test cannot identify anatomical changes Evaluation of treatment response such as strictures, which are best delineated with endoscopy Spondylodiscitis and contrast radiography. It is less sensitive for disease affect- Para-vertebral soft tissue infection in spondylodiscitis ing the upper tract than the lower gastrointestinal tract and may also be affected by steroid administration [32, 33]. Clinical indications for nuclear medicine evaluation: Joint prosthesis and other orthopedic hardware & Evaluation of activity of disease More than a million hip replacements are performed each year & Evaluation of extent of disease worldwide, and the number of other artificial joints (shoulder, & Differential diagnosis between inflammatory and fibrotic elbow, hip, knee) inserted is also rising. With increasing num- strictures bers of implantations, mechanical and infected loosening of & Early assessment of disease relapse after surgery the prostheses have become more common. The risk of infec- & Evaluation of treatment response tion is highest during the first two years after implantation. Differentiating infection from aseptic loosening is difficult because the clinical presentation and the histopathological changes in both entities can be similar, but at the same time Fever of unknown origin is extremely important because the treatment of these two entities is different. Joint aspiration with gram stain and cul- Fever of unknown origin (FUO) is defined as a body ture is considered the definitive diagnostic test; its sensitivity, temperature higher than 38.3 °C persisting for two weeks however, is variable, ranging from 28 to 92%; specificity is or more, remaining unexplained after 3-day inpatient or more consistent, ranging from 92 to 100%. Plain radiographs two-week outpatient observation. Beside the classical are neither sensitive nor specific and cross-sectional imaging ‘pure’ FUO, Durack identified related conditions modalities (CT and MRI) are limited by hardware induced encompassing neutropenic FUO, HIV-associated immune depression FUO and nosocomial FUO [34]. Diagnosis is artifacts. Radionuclide imaging (both WBC and anti-G-mAb scintigraphy) that is often not affected by metallic hardware often made by a good anamnestic assessment with special can play an important role in the diagnosis of prosthetic joint attention to occupational and recreational exposure to infection. The evaluation of hybrid images (SPECT/CT) can pathogens, a recent travel history or drug abuse. be also performed after imaging reconstruction without atten- Laboratory tests are also relevant but may be very unspe- uation correction, with an overall accuracy ranging from 88 to cific and radiological imaging may be helpful although in 98% (being highest for WBC combined with bone marrow most cases the origin of FUO remains uncertain [34]. imaging) [21, 27–30]. Scintigraphy with labeled WBC and PET with [ F]FDG Clinical indications for nuclear medicine evaluation: are additional imaging modalities to evaluate patients with FUO with high sensitivity, thus a negative study virtually ex- & Suspected septic loosening cludes an infection as the cause of the fever [35–38]. It is & Evaluation of extent of infection accepted that when patients with FUO have low probability & Evaluation of treatment response of infection (low ESR, WBC count and CRP) the first scan to & Suspected infective post-traumatic pseudo-arthrosis be performed should be [ F]FDG. If patients have a high & Exclusion of infection in patients with antibiotic spacer clinical probability for infection they should first perform a before prosthesis re-implant WBC scan. There are also reports on the use of radiolabelled anti-granulocyte mAb in FUO with comparable diagnostic accuracy as for WBC. Inflammatory bowel diseases Clinical indications for nuclear medicine evaluation: Inflammatory bowel diseases (IBD) mainly include Crohn’s & Evaluation of unknown site of infection in patients with Disease (CD) and Ulcerative Colitis (UC). Ultrasound (US), high pre-test probability of infection CT and MRI are of particular use in evaluating the presence of & Evaluation of extent of disease Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 1819 Soft-tissue infections pulmonary uptake is caused by technical artifacts caused by faulty labelling or reinjection and is usually not associated Postoperative infections Nuclear medicine procedures can be with infection and disappears within 4 h post injection. a useful adjunct to morphologic imaging and can facilitate the Clinical indications for nuclear medicine evaluation: differentiation of abscesses from other fluid collections, tu- mor, and normal postoperative changes. Labeled WBCs rarely & Diagnosis of bacterial pneumonia accumulate in uninfected tumors and do not, with few excep- & Differential diagnosis of infective and neoplastic lesions tions, accumulate in normally healing surgical incisions & Evaluation of treatment response [39–41]. Consequently, because of this high specificity, WBC imaging is the preferred radionuclide test for the evalu- ation of postoperative infections [42]. Central nervous system infections The differential diagnosis of a contrast enhancing brain lesion identified on CT or MRI Cardiovascular system infections Echocardiography is readily includes abscess, tumor, cerebrovascular accident, and even available and accurately diagnoses bacterial endocarditis. multiple sclerosis. WBC scintigraphy provides valuable infor- Nevertheless, the use of radiolabelled WBC scintigraphy accu- mation in the differential diagnosis of contrast enhancing rately detects infective endocarditis and extra-cardiac septic brain lesions [55–61] and in the follow-up of patients with embolisms [43–47]. Prosthetic vascular graft infections are also malignant otitis. False negative results have been reported in first studied by angio-CT, and labeled WBC imaging is a useful patients receiving high doses of steroids [61]. The use of anti- complement [48–52]. The accuracy of WBC imaging for diag- G-mAb can also be useful in these situations [62, 63]. nosing prosthetic vascular graft infection is above 90%, and the Clinical indications for nuclear medicine evaluation: use of [ F]FDG is also a highly accurate alternative [53]. No role of WBC scan has been suggested for imaging vasculitis. & Cerebral hypodensity CT lesions with hypervascularized Clinical indications for nuclear medicine evaluation: peripheral ring & Differential diagnosis of cerebral lesions in HIV patients Infective endocarditis (IE) Suspected IE with doubtful ultrasound Evaluation of septic embolism in certain IE Other applications of radiolabelled WBC and mAbs Evaluation of treatment response Differential diagnosis with marantic vegetations Aids WBC scintigraphy plays a limited role in the evaluation of Vascular graft infections AIDS-related infection. The test is not as sensitive as CT for Diagnosis of infection detecting opportunistic infections of the lungs and lymph nodes. Evaluation of extent of disease The test is useful, however, for detecting colonic infections in Evaluation of disease activity the HIV(+) patient [64–66]. It must be kept in mind that han- Evaluation of treatment response dling blood from HIV-infected patients carries a risk for both the staff and fellow patients if multiple labelling procedures are performed at the same time, and recommendations regarding Pulmonary infections Although pulmonary uptake of labeled this specific issue have been previously published [1, 67, 68]. WBC is a normal event during the first few hours after injec- tion, its appearance after 24 h is abnormal. Diffuse pulmonary activity on images obtained more than Image acquisition protocols 4 h after injection of labeled WBC can be due to opportunistic infections, radiation pneumonitis, pulmonary drug toxicity The use of anti-G-mAb and WBC scintigraphy has many use- and adult respiratory distress syndrome. A diffuse pulmonary ful fields of application. Nevertheless, the image acquisition uptake pattern is also seen in septic patients with normal chest protocols are not always identical, and in addition, there may radiographs who have no clinical evidence of respiratory tract be some variation in the criteria used in image interpretation. It inflammation or infection. It is important to note that while is therefore important to standardize, based on published evi- diffuse pulmonary activity on labeled WBC images is associ- dence and on the experience of the authors, the acquisition and ated with numerous conditions, it has been only very rarely interpretation protocols for each disease. Therefore, the aim of described in bacterial pneumonia [54]. Focal pulmonary up- this guideline is to provide general recommendations for im- take that is segmental or lobar is usually associated with bac- proving clinical practice and to minimize the occurrence of terial pneumonia. This pattern can be also seen in patients with artifacts and interpretation hurdles. cystic fibrosis and is due to WBC accumulation in pooled For all studies using labeled blood products, it is essential secretions in bronchiectasic regions. Non-segmental focal that measures are in place for correct patient identification in 1820 Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 99m order to avoid cross-administration of labeled cells to the For Tc labeled anti-granulocyte mAbs scintigraphy ear- wrong patient [7, 8]. ly lung images are not necessary but (as applicable) planar, The potential interference of some drugs and antibiotics SPECT (or SPECT/CT) and whole-body images at 3–4hand with cell labelling has to be considered [67, 68]. However, 20–24 hshouldbe performed. patients receiving antibiotic treatment should not be excluded According to different biodistribution of labeled WBC in Bapriori^ since reports regarding their effect on WBC scin- blood, bone-marrow, infection and sterile inflammation, three tigraphy give various results. While several authors describe sets of images must be generally acquired of the region of no interference between such treatment and the accuracy of interest: Bearly images^ (within30 minand1hp.i.), Bdelayed WBC/mAbs scanning, others advise delaying the scan for at images^ (between 2 h and 4 h p.i.) and Blate images^ (between least 1–2 weeks after therapy withdrawal or, in the case of 20 h and 24 h p.i.). Early images provide useful information doubtful study results in patients receiving antibiotics, to re- on the lung transit, on liver/spleen ratio (which should be at peat the test 2 weeks later. The decision whether to perform or least 1:2 but may also depend on the neutrophil:eosinophil cancel the study depends entirely on the clinical setting and ratio since neutrophils preferentially migrate in the liver and must be discussed case-by-case with the referring physician. eosinophils; that uptake HMPAO much more avidly than neu- trophils, preferentially migrate in the spleen) on bone marrow 99m Acquisition protocols for Tc-labeled WBC and anti-G-mAb distribution and on vascular pattern. Sites of infection should scintigraphy be visible on delayed images with further accumulation of labeled leukocytes seen in the late images due to increased A large-field-of-view gamma camera with a low-energy high- uptake in infected areas and reduction in background activity. resolution collimator should be used. Camera resolution Over time there is also reduction or stable activity in bone should always be set to zoom 1 at 512 × 512 pixels with a marrow and non-specific activity in the bowel due to Tc- HMPAO excretion from the liver. high resolution collimator. 99m For Tc labeled WBC studies, an in vivo quality control Several acquisition protocols have been suggested for both 99m Tc-labeled WBC and anti-G mAb scintigraphy. Fixed should be performed including imaging of lungs, liver and spleen at 30 min post-injection (p.i.) (early images). Normal counts per image or fixed times per image at all time points bowel activity is seen in 20–30%of children at 1hand 2–6% are the most commonly used protocols but also the most dif- of adults at 3–4 h p.i. According to the clinical indication, ficult to be interpreted because of interference of radioactivity whole-body, planar and, if appropriate, SPECT (or SPECT/ from other organs and operator bias in image display. For CT) images should be performed at 3–4 h (delayed images) fixed counts or time acquisitions, images of the regions of and 20–24 h (late images). interest are acquired for at least 500,000 counts or 5–10 min 99m 111 Table 1 How to calculate acquisition time according to decay of Tc (A) and In (B) a 99m Hours Acquisition time (seconds) for Tc decay corrected images exp(-λt) λt 0 100 150 200 300 (Early images) 1 112 168 224 337 0.8909 0.1155 2 126 189 252 378 0.7937 0.231 3 141 212 283 424 0.7072 0.3465 4 159 238 317 476 0.6300 0.462 6 200 300 400 600 0.5001 0.693 8 252 378 504 756 0.3969 0.924 14 504 756 1008 1511 0.1985 1.617 20 1007 1511 2015 3022 0.0993 2.31 22 1269 1904 2538 3808 0.0788 2.541 a 111 Hours Acquisition time (seconds) for In decay corrected images exp(-λt) λt 0 100 200 300 400 (Early images) 1 101 202 303 404 0.9897 0.0103 2 102 204 306 408 0.9795 0.0206 3 103 206 309 413 0.9694 0.0310 4 104 208 313 417 0.9595 0.04137 6 106 213 319 426 0.9398 0.06205 8 109 217 326 435 0.9206 0.08274 14 118 236 354 472 0.8475 0.16549 20 123 246 369 492 0.8131 0.20686 22 125 250 374 499 0.7965 0.22755 Time 0 is the time of the first scan not necessarily the time of injection Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 1821 with a large field of view including a region of normal bone producing false positive images at later time points. Only in marrow as a reference (e.g. iliac bone, sternum or skull). cases with a suspected fistula or abscess it is necessary to These methods, and particularly the acquisition of several acquire images at a later time point, at 4–6 h after radiophar- images at several time-points with the same amount of counts, maceutical injection (or even 20–24 h post injection). This is discouraged or recommended for expert readers. pitfall does not occur with In-labeled WBC that are there- In order to reduce operator dependence in image display fore preferable for studying abdominal infections. For the 99m and final interpretation, we recommend acquiring images same reason, when using Tc-labeled WBC, vascular graft time-corrected for isotope decay (see Table 1). If early images infections of abdominal vessels (aorto-bi-iliac grafts) should are acquired with a set number of counts or time, delayed and be imaged within 3 h from administration of labeled cells. A late images should be corrected for the isotope half-life. With dynamic acquisition (one image every 5 s for the first 150 s this acquisition modality, different images can be compared after injection) may help to map the vascular structures and with the same intensity scale, in absolute counts (and not in % detect obstructions or aneurisms. For all these intra-abdominal of maximum activity) thus avoiding any operator bias [1]. and pelvic infections, SPECT/CT can be extremely helpful (if This method also allows to correctly detect a true increase of not mandatory), allowing for a precise localization of an infec- uptake in suspected regions over time, an important criteria of tious focus to the vascular graft or adjacent soft tissues only. positivity for bone infections and for most soft tissue infec- With anti-G-mAbs, image protocols differ between com- 99m tions. The method has been recently validated in a multicentre plete and fragmented antibodies: images with complete Tc- European study [69, 70] as being highly accurate for osteo- anti-NCA-95 antibody should be performed at 2–4 h p.i. and myelitis, prosthetic joint infections, diabetic foot osteomyelitis 16–24 h p.i. in planar whole body technique because a signif- and some soft tissue infections (such as dermal filler infec- icant increase in sensitivity and specificity will be achieved tions, endocarditis, abscesses, brain infections and sternal with delayed 24 h images due to higher target to background wound infections) but not for soft tissue infection in diabetic ratios (T/B). Planar images can be performed with an acquisi- foot [14, 71]. tion protocol time-corrected for isotope decay, as mentioned SPECT or SPECT/CT is useful in most types of infection above for WBC. The best time point for SPECT images is 4– but should be considered mandatory in a few selected indica- 6 h after injection but another SPECT at 16–24 h p.i can also tions (e.g. endocarditis, diabetic foot, vascular prosthesis). If be performed if required, similarly to WBC scan. 99m SPECT or SPECT/CT is used for quantitative purposes, this With Tc-anti-NCA-90 (Fab’) antibodies, images should should be acquired in a 128 × 128 matrix utilizing the same be performed 1 h p.i. and 4–6 h p.i. in whole body as well as in decay-corrected protocol as described above (i.e. 5 h post- single scan technique. Acquisition protocols are also better injection for 7 s/step and 20 h post-injection for 40 s/step, using time-corrected for isotope decay. SPECT of suspected because of 15 h difference between the two scans). If acquired central bone infection should be performed at 4–6 h p.i., with a decay-corrected protocol, SPECT images can also be whereas in case of suspected endocarditis delayed SPECT used for semi-quantitative purposes to evaluate any increase images at 16–24 h p.i. have also been suggested [45]. The 99m of T/B ratio with time. combination of Tc-anti-NCA-90 (Fab’) antibodies and 99m Typically, however, a SPECT/CT is performed after planar Tc-HDP three phase bone scan can be useful to rule out images (4 or 5 h post injection) only to provide the best ana- false positive accumulation of the antibody fragment due to tomical localization of WBC accumulation, but the positivity non-specific inflammatory oedema. Others have suggested for infection is given by comparing delayed and late planar also performing late images 20–24 h after injection to improve images. Therefore, the SPECT/CT is not required for semi- the specificity [72, 73], although this protocol and the speci- 99m quantitative purposes and acquisition at 4–5 h p.i. can be ac- ficity of Tc-anti-NCA-90 (Fab’) antibodies have been crit- quired with 20–30 s/step (depending on the injected activity) icized by others [74, 75]. and acquisitions at 20–24 h p.i. are often not necessary (even For both antibodies, as for labeled WBC, SPECT/CT because would require a very long acquisition time) but can be should be considered mandatory for endocarditis, diabetic foot also performed if new sites of pathological uptake appear that and vascular prosthesis. were not detected at 4–5 h scan (in this case acquisition time should be at least 30–50 s/step, also depending on the injected Acquisition protocols for In-labeled WBC scintigraphy activity and on the region to be imaged, with time longer for peripheral parts and shorter for the abdomen). A large-field-of-view gamma camera with a medium energy 99m 111 When using Tc-HMPAO-labeled WBC for abdominal collimator should be used. Both In photopeaks should be infections and IBD, images should only be acquired at 30 min acquired at 173 and 245 keV (±10%). If using a time-saving 99m and 2–3 h after injection of the labeled WBCs. This is because acquisition protocol with both Tc-colloid for bone marrow 99m 111 a metabolite of Tc-HMPAO is released by WBC with time, imaging performed in orthopedic cases prior to In-WBC re- taken up by the liver and excreted via the bowel, thus injection, only the upper peak of In should be subsequently 1822 Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 99m acquired (245 keV) to avoid cross-contamination of Tc performed at the end of the WBC/mAb study (same day of the into the lower peak of In. This will obviously reduce the 24 h image or in the next few days) by injecting i.v. about 99m statistics but improve the specificity [28, 29]. 185 MBq (5 mCi) of Tc-colloids (colloids of greater than Images of the chest, abdomen and pelvis should be obtain- 500 nm are recommended) and acquiring images of the region ed for at least 100,000 counts but images over the peripheral of interest after a minimum of 20–30 min and a maximum skeleton may be acquired for time. As described above for time of 6 h p.i. Images should be performed of the same views 99m Tc, time presets decay-corrected can be used (see Table as those acquired with WBC/mAbs although the acquisition 99m 1), although they are less relevant than for Tc due to the time should be limited to 300 s (if performed immediately at 111 111 long half-life of In. As In-WBC scintigraphy is prefera- the end of WBC/mAbs scan) or 500,000 counts (if performed ble in low-grade infection, delayed and late imaging is usually one or more days after WBC/mAbs scan). Another option in 99m sufficient and is not impaired by elution of the radiolabel from patients with violated bone is to perform Tc-colloid mar- WBC. In abdominal infections or IBD, early imaging may be row imaging simultaneously with WBC scans if labelling is 111 111 useful to differentiate between mucosal uptake that will de- done with In-oxine/tropolone. In this case, during In- crease with time with intraluminal transit, sub-mucosal uptake WBC imaging only the upper peak of the In emissions that remains stable, and abscess that will show increasing should be used [28]. uptake between 3 and 4 h and 20–24 h p.i. Given the low statistics due to the limitations in the injected activity for do- Interpretation criteria for WBC and anti-G-mAbs simetry reasons, SPECT or SPECT/CT may have to be per- formed with prolonged acquisition times. The very low back- Given a correct acquisition protocol, images must be correctly ground activity will nevertheless allow high contrast with such displayed on the screen to allow their correct interpretation. acquisition settings, even with low statistics. When using In-labeled WBC for IBD evaluation, stool Most work stations are pre-set to display multiple images in % of maximum counts/pixel. This display does not allow the collection and counting at early and late time point may indi- cate the presence of radiolabelled cells migrating from infect- reader to evaluate modifications of activity with time in the regions of interest. Furthermore, this kind of display needs the ed mucosa to the lumen, an indirect sign of inflamed bowel. Planar acquisition of the pelvis in outlet views (namely, with reader to adjust the intensity scale of each image to make bone marrow activity comparable and therefore introduces an oper- the patient sitting above the gamma camera) or SPECT/CT may discriminate better between rectal and bladder activity in ator bias [1, 69, 70]. All images acquired at different time points must be case of suspected recto-sigmoidal extent of IBD [32, 33]. displayed with the same intensity scale in absolute counts, when they have been acquired with a time-decay corrected Acquisition protocol for bone marrow scintigraphy (for bone protocol. Any adjustment of the intensity scale must be ap- and prosthetic joint infection) plied to all images together, thus avoiding any operator bias. Further interpretation of labeled WBC/mAb scintigraphy Bone marrow scintigraphy is usually performed in doubtful requires knowledge of the normal variants and pitfalls of these WBC scans for bone and prosthetic joint infections. These are studies. The normal biodistribution of the Table 2 Normal biodistribution of radiopharmaceuticals 99m 99m 99m 111 99m Location Tc-WBC Tc-WBC Tc-WBC In-WBC Tc-mAbs early (30′-1 h) delayed (3-4 h) late (20-24 h) (3 h/24 h) (3 h/24 h) Blood/heart +++ + – ±± Lung + –– −/−−/− Liver ++ ++ ++ ++/++ +++/+++ Spleen +++ +++ +++ +++/+++ +/++ Kidneys + + + −/− +/+ Bladder – ++ −/− +/+ Bowel – +++ −/− −/− Bone marrow + ++ ++ ++/++ +++/+++ a 111 With In WBC any bowel activity is abnormal; swallowed neutrophils from upper and lower respiratory tract could be considered in some cases of mild bowel activity Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 1823 radiopharmaceuticals has been summarized in Table 2,with Since labeled WBC and anti-G-mAb scintigraphy have a uptake ranging from – (no activity) to +++ (the most intense very high sensitivity, a negative scan (when there is no in- activity). Diagnosis of infection is made by comparing de- creased uptake of WBC with time) is sufficient to exclude layed (3–4 h) and late images (20–24 h). the presence of bone infection. Images are then classified as (a) negative, when there In case of equivocal qualitative analysis, a semi-quantitative is no uptake or there is a clear decrease of activity from analysis should be performed, and only in case of equivocal delayed to late images in the regions of interest, (b) quantitation (less than 10% increase of T/B over time) bone positive, when a clear increase is seen with time of up- marrow imaging must be used. Colloids, anti-G-mAbs and la- take intensity or size in the regions of interest, and (c) beled WBC accumulate in healthy and displaced bone marrow, equivocal, in all other situations. For OM in general, the whereas, in infection sites, colloids do not accumulate. early images at 30 min p.i. should be considered as a The WBC or anti-G-mAb scintigraphy is positive for Bvascular/bone marrow phase^.Itis usefultocompare osteomyelitis when there is activity on the primary scan it with the distribution of bone marrow. It must therefore without corresponding activity on the bone marrow im- be seen as a qualitative image and not considered for age. When any other pattern is present, the study is neg- quantitative analysis compared to delayed and late im- ative for infection [13, 28, 69]. ages [1, 69, 70]. There are sufficient evidence based data to support the use There might be several reasons for defining a set of images of both WBC and anti-G-mAb for the diagnosis of PJI and as Bdoubtful^. These are: similar or slightly decreasing uptake OM as well as for FDG-PET/CT, only for OM and not for PJI. with time in the regions of interest (intensity or size); increase One particular mention deserves the diagnosis of ster- of bone marrow with time that does not allow to easily eval- nal wound infections (SWI) after thoracotomy and the uate suspected regions; slight increase in size over time with- criteria for the differential diagnosis between superficial out an increase in intensity of uptake; slight increase in size infection (that requires medical treatment) and deep infec- and/or intensity over time in the region of interest but with a tion (that may require surgical treatment). In particular, if similar increase over time of bone marrow activity; activity in planar images at 3 h and 20 h are considered, a linear region of interest that remains unmodified with time (in size homogeneous uptake that decreases with time or remains and/or intensity) with bone marrow activity that increases or stable over time can be considered as no infection or su- decreases over time. perficial infection. An inhomogeneous uptake with areas In all doubtful cases, following visual assessment, a semi- of increased uptake over time can be considered as an quantitative evaluation can be performed for the differential infection, most likely a deep infection and rarely a super- diagnosis of infection from non-specific uptake [69, 71, 76, ficial infection. SPECT/CT acquisition can also be of help for the correct evaluation of the extent of infection. 77]. Regions of interest (ROIs) are drawn over the area of interest (usually with the highest uptake) and copied to a pre- sumed normal reference tissue; contra-lateral bone is the best Diabetic foot (DF) In diabetic foot, to identify a Charcot foot an when available [69]. The mean counts per pixel in these ROIs additional scan with colloids for bone marrow imaging is are recorded and used to calculate the lesion-to-reference (L/ mandatory to differentiate between expanded bone marrow R) ratio in both the delayed and late images (L/R and L/ (a common finding after many surgical interventions to the delayed R , respectively). When the L/R ratio increases with time (L/ bone as well as in Charcot foot) and OM [13, 14, 28]. There late R >L/R ) by at least 10%, the study can be considered are sufficient evidence based data to support the use of both late delayed indicative of infection; when the L/R is similar or decreases WBC and anti-G-mAb for the diagnosis of DF as well as for late slightly with respect to L/R the examination can be clas- FDG-PET/CT. delayed sified as equivocal; and when L/R is significantly decreased late compared to L/R (L/R <L/R ) the examination Inflammatory bowel diseases (IBD) Radiolabelled autologous delayed late delayed can be classified as negative for infection [69, 76]. WBC are a second-line imaging technique in IBD diagnosis If SPECT/CT is performed the delineation of the site of used in case radiological and/or endoscopic exams are incon- increased radiopharmaceutical uptake may be calculated by clusive [31]. The absence of abdominal uptake of WBC ex- a 50% isocontour on a single transaxial slice that shows the cludes the presence of IBD while the presence of pathological site with the highest uptake (the lesion) and the reference uptake can be due to IBD or to other disorders. WBC scintig- normal tissue. The same criteria as described above can be raphy is positive when there is an increase of uptake of WBC used for imaging classification. in delay images (2–3 h p.i). Differential diagnosis between UC and CD is possible according to the pattern and localisation of Prosthetic joint infection (PJI) and peripheral bone osteomy- the WBC uptake: if the uptake is in the ileo-cecal area, in the elitis (OM) The above described criteria should be used for the small bowel and there is a patchy distribution of radioactivity, it is more indicative of CD. Otherwise, when the leukocytes diagnosis of peri-prosthetic joint infection and osteomyelitis. 1824 Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 uptake is focused in left colon up to the rectum, or diffuse Fever of unknown origin (FUO) Labeled WBC scan is usually uptake in the colon, it is more characteristic of UC. If there adopted as second-line diagnostic investigations in the diag- is a colon uptake alone, it is not possible to establish a certain nosis of FUO, even if their overall performance is very satis- differential diagnosis. Major indications for WBC scan in IBD factory. The pre-test probability of infection is important and patients are: the early assessment of recurrences after surgery in case of low pre-test probability of infection (based on rou- and the differential diagnosis between inflammatory and fi- tine blood tests) an FDG-PET/CT scan is the preferred choice. brotic strictures, the first being positive and the second nega- In case of high white blood cell counts, ESR or CRP values a tive. There are no sufficient evidence based data to support the WBC scan can be performed as first imaging modality. use of anti-G-mAb scan in IBD. Indeed, due to high sensitivity and specificity of WBC scin- tigraphy (60–85% and 78–94%, for In-oxine; 96 and 92% 99m Vascular graft prosthesis infection (VGI) Radionuclide imag- for Tc-HMPAO), this can be considered the procedure of ing studies are usually complementary to radiologic im- choice in patients with FUO with high probability of infection aging, and limited to those patients with equivocal con- [78–80]. By contrast, there are no sufficient evidence based 99m ventional imaging. Tc-HMPAO-WBC scintigraphy has data to support the use of anti-G-mAb scan in FUO. Image shownveryhighsensitivityand specificity in the evalua- interpretation criteria depends on the region of pathologic up- tion of vascular prosthesis infection based on the presence take of the labeled WBC, according to that mentioned above. of pathologic accumulation of labeled WBC in the site of infection as early as 2–3 h post-injection [49]. As previ- Pulmonary infections (PI) There are too few reports (mainly ously described, early dynamic images and oblique im- case reports or AIDS patients) to define a specific imaging ages are useful integration to antero-posterior whole body protocol for pulmonary infections. Planar antero-posterior im- scans, but SPECT or SPECT/CT images are often manda- ages are generally sufficient, given the considerations and pit- tory to discriminate the exact location of any suspicious falls mentioned above. uptake seen in planar images. There are sufficient evidence based data to support the use Central nervous system infections (CNS) Scintigraphy with of both WBC and of FDG-PET/CT in VGI. radiolabelled WBC has shown to be very sensitive and spe- cific in CNS infections and other head and neck infections Infective endocarditis (IE) Nuclear medicine imaging tech- such as malignant otitis, sinusitis, dermal filler infections niques may be of great value in cases of undetermined echo- and skull osteomyelitis [55–63, 71]. Due to high physiological cardiographic findings (i.e., artifacts deriving from mechani- brain uptake of FDG, to date, WBC scintigraphy is the only cal prosthesis) in the suspicion of an infective endocarditis and and most accurate nuclear medicine technique for H&N infec- in detecting septic embolism (ref EHJ). Scintigraphy with la- tions. Planar antero-posterior images and latero-lateral images beled WBC should be performed always with SPECT/CT are often sufficient but SPECT and SPECT/CT acquisitions acquisition that enable obtaining high resolution images of can be mandatory in some low grade infections [71]. the thorax. When there is a progressive accumulation of Image acquisition protocols and interpretation criteria are WBC in the cardiac region (for example, valve leaflets) the summarized in Tables 3, 4 and 5. scintigraphy is positive. WBC scintigraphy is negative when there is no pathological uptake of WBC in the cardiac region Additional strategies that may improve accuracy while it is equivocal when there is a stable or decreasing ac- cumulation of labeled cells. Since two SPECT acquisitions If SPECT/CT is not available SPECT WBC or anti-G-mAb must be performed (usually at 5 h and 20 h post-injection) images can be co-registered with separately acquired CT or the acquisition time of each examination can be calculated MRI images (usually transaxial slides) for a more accurate according to isotope decay, in order to have the same statistics localization of the pathological uptake, but attention should in both images and avoid operator bias in the interpretation of be paid to the fact that thickness of SPECT and CT slides is findings. Total body scans at 3–4 h and 21 h post-injection different. (before and after SPECT acquisitions, respectively) should New software is also available for SUV calculation on also be performed to detect possible septic embolisms [2, SPECT images. 46, 47]. For prosthetic valves, it is important to analyze both CT-attenuated and non-attenuated (NAC) images since the Physiologic biodistribution, pitfalls and artifacts positivity at NAC excludes a false positive finding due to metallic artifacts. After in vivo administration of radiolabelled WBC, the cells There are sufficient evidence based data to support the use normally show a transitory migration to the lungs of both WBC and FDG-PET/CT for IE but not for the use anti- (margination) and then accumulate in the spleen and, to a G-mAb. lesser extent, in the liver and bone marrow, with a maximum Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 1825 Table 3 Summary of acquisition/interpretation protocols of musculoskeletal infections Examination Acquisition protocol Image interpretation Pitfalls Osteomuscular Labeled WBC and Qualitative analysis: Assess timing after surgical procedure. 99m (osteomyelitis, Tc-mAb-anti-granulocy- Infective lesions show an uptake that arise over Assess the presence of artifacts related to the and prosthetic tes: time while aseptic flogistic lesions show a attenuation over-correction in patients with joint infection) 30 min p.i. planar images for decreasing uptake over time. In doubtful cases metallic devices QC and ROI it is necessary to compare the images with 99m -3-4 hp.i.total-body and pla- Tc-sulfur colloids: infective lesion shows a nar images ROI mismatch pattern of radiopharmaceutical 20-24 h p.i.: planar and uptake. SPECT(/CT) ROI Semi-quantitative analysis: 99m - Tc-sulfur colloid Calculate the target/background ratio drawing 20–360 min p.i. planar images ROI on the regions that show an increased ROI uptake over time (T) and on contralateral bone marrow (B) FP results can be obtained if the scintigraphy is performed within 3–4 months after surgery 99m Discitis, spondylitis Tc-HDP/MDP: Clinical history (timing from surgical procedure, Assess timing after surgical procedure. and i.v. injection during dynamic and type of metallic implant, etc). Assess the presence of artifacts related to the spondylodiscitis acquisition Anatomic location of tracer uptake. attenuation over-correction in patients with 99m 67 4 h p.i. total-body, planar and Tc-HDP/MDP + Ga-citrate: metallic devices SPECT(/CT) images ROI Infective lesions show usually greater uptake of 67 67 99m Ga-citrate Ga in comparison to Tc-HDP/MDP while 4 h p.i. total body, planar and an aseptic process (arthritis, fracture etc) shows 99m SPECT(/CT) images ROI greater uptake of Tc-HDP/MDP than that of 24 h p.i. planar images ROI Ga. 48 h p.i. planar and [ F]FDG PET/CT: SPECT(/CT) images ROI, Infective lesions show greater uptake of if necessary [ F]FDG than healthy vertebral body [ F]FDG PET/CT 1 h p.i. PET/CT Sternal infections Labeled WBC and Qualitative analysis: Medicate the wound before scintigraphic 99m Tc-mAb-anti-granulocy- an increased uptake with time of sternum and/or acquisition to avoid FP results. tes: mediastinum is indicative of infection. FP results: 30 min p.i. Planar images for Semi-quantitative analysis: missed clearing of wound before scintigraphic QC and ROI Pattern I: Presence of deep infection. Widespread acquisition 3–4 h p.i. total-body, planar and intense uptake of the sternum, greater than and SPECT(/CT) images liver uptake, after 3–4and 20–24 h. ROI. Pattern II: Presence of superficial infection. 20–24 h p.i. planar and Moderate increase or irregular uptake of SPECT(/CT) images ROI sternum that does not change or decrease between 3 and 4 and 20–24 h. Pattern III: Absence of infection. Medium intensity uptake with uniform distribution of the sternum, abnormal uptake (Bcold^ areas) on the midline or cold areas with focal distribution in the midline Diabetic foot Labeled WBC and Semi-quantitative analysis: Clean the wound before scintigraphy 99m Tc-mAb-anti-granulocy- Infective lesions show an uptake that rises over acquisition to avoid FP. Assess the presence tes: time while aseptic flogistic lesions show a of lesions of size lower than spatial 30 min p.i. planar images for decreasing uptake over time. In doubtful cases resolution of method QC and ROI it is necessary to compare the images with 99m 3–4 h p.i. total-body and pla- Tc-sulfur colloids infective lesion to check nar images ROI for a mismatch pattern of radiopharmaceuticals 20–24 h p.i. planar and uptake SPECT(/CT) images ROI 99m Tc-sulfur colloids 20–360 min p.i. planar images QC quality control, ROI region of interest uptake at 2–4 h p.i.. Labeled neutrophils accumulate prefer- spleen. During the following hours, labeled cells migrate from entially in the liver and eosinophils preferentially into the spleen and bone morrow to infected tissues. This is the reason 1826 Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 Table 4 Summary of acquisition/interpretation protocols of soft tissues infections Examination Acquisition Image interpretation Pitfalls protocol Central nervous system Labeled WBC: Semi-quantitative analysis: infections 30 min p.i. planar images for Infective lesions show usually an uptake equal to QC and ROI +++/++++ while aseptic lesions show no uptake or equal 3–4 h p.i. total-body and pla- to +/++ nar images ROI 20–24 h p.i. planar and SPECT(/CT) images ROI Infective endocarditis Labeled WBC: Qualitative analysis: Assess the presence of artifacts related to the attenuation overcorrection for the 30 min p.i. planar images for analysis of cardiac region (valve plans) and other regions presence of surgical implants (mechanical valve prostheses and CIED). QC and ROI (CNS, spleen and axial skeleton, lung) FN results: 3–4 h p.i. total-body, planar Anatomic location of WBC uptake. fungal endocarditis and SPECT(/CT) images Correlation with flogosis markers and echocardiography. FP results: ROI atherosclerotic plaques, sarcoidosis, tumor, vasculitis etc 20–24 h p.i. planar and SPECT(/CT) images ROI Clinical history (date and sort of surgical procedure). Assess the presence of artifacts related to the attenuation overcorrection in Post surgical infections (dermal Labeled WBC: filler infections and 30 min p.i. Planar images for Anatomic location of WBC uptake. patients with metallic devices abscesses) QC and ROI Correlation with flogosis markers 3–4 h p.i. total-body, planar and SPECT(/CT) images ROI 20–24 h p.i. planar and SPECT(/CT) images ROI Pulmonary infections Labeled WBC: Focal pulmonary uptake that arise over time is usually FP results: 30 min p.i. Planar images for associated with bacterial pneumonia. cystic fibrosis, faulty labelling or reinjection QC and ROI Diffuse pulmonary activity on images obtained 4 h p.i. can 3–4 h p.i. total-body planar be due to opportunistic infections, radiation pneumonitis, and SPECT(/CT) images pulmonary drug toxicity and adult respiratory distress ROI syndrome 20–24 h p.i. planar and SPECT(/CT) images ROI QC quality control, ROI region of interest Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 1827 Table 5 Summary of acquisition/interpretation protocols of others infections Examination Acquisition Image interpretation Pitfalls protocol 99m Fever of Labeled WBC and Tc-mAb-anti-granulocytes: Evaluation of all regions of increased uptake having regard to Assess the presence of artifacts related to the attenuation unknown 30 min p.i. planar images for QC and ROI the overcorrection in patients with metallic devices or prostheses origin 3–4 h p.i. total-body and planar images ROI possible differential diagnosis (inflammation, cancer) 20–24 h p.i. planar and SPECT(/CT) images ROI 99m Inflammatory Labeled WBC and Tc-mAb-anti-granulocytes: Abscesses and fistulae can appear only at late images. Better Starting from 3 h p.i. due to aspecific accumulation of secondary bowel 30 min-1 h p.i. planar images for QC and ROI to hydrophilic complexes of Tc in caecum and ascending colon diseases 2–2.5 h p.i. planar and SPECT(/CT) images ROI use SPECT/CT in case of doubt. after 2 h p.i. planar image of the chest (in patients with suspected FP results can be obtained in tumor. Aspecific uptake in oesophageal localization of disease). colitis, bleeding and diabetic patients 99m 24 h p.i. planar images ROI for Tc mAb or for abscesses and fistulae 99m Vascular Labeled WBC and Tc-mAb-anti-granulocytes: Clinical history (date and sort of vascular prosthesis implant, Assess the presence of artifacts related to the attenuation prosthesis i.v. injection during dynamic acquisition (one image every etc). overcorrection in patients with metallic clips. 5–10 s for 3–5min) Anatomic location of WBC uptake (in vascular prosthesis FN results: 30 min p.i. planar images for QC and ROI wall, chronic flogistic process with low recruitment 3–4 h p.i. total-body, planar and SPECT(/CT) images ROI at the site of surgical clips and/or in soft tissues) of WBC 20–24 h p.i. recommended if the chest is the ROI QC quality control, ROI region of interest 1828 Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 why bone marrow activity decreases with time and infection antibodies, the uptake of liver > spleen, and very intense up- shows an increase of activity with time. Although pulmonary take is seen in the kidneys due to predominantly renal excre- 99m uptake of labeled WBCs is physiologic during the first few tion of Tc-anti-NCA-90 (Fab’) and non-specific bowel ac- hours after injection, at 4 and 24 h p.i. such lung activity is tivity is already seen 4–6 h p.i. due to enzymatic liver degra- abnormal. Focal segmental or lobar pulmonary uptake is also dation of the compound. associated as a rule with infection. Non-segmental focal pul- Monoclonal antibodies allow rapid and safe delineation of monary uptake in early images, however, is usually caused by inflammatory foci by efficient accumulation on the surface of technical problems during labelling or reinfusion and is gen- chemotactic activated granulocytes. The decrease of molecu- erally not associated with infection. lar size increases the background clearance together with a Cell migration is largely influenced by the vascularization significant reduction of non-specific accumulation in other on the infected region. In spondylodiscitis there a reduced organs hampering image interpretation. Antibodies bind to blood flow due to oedema that compresses small capillaries granulocytes with high affinity (with K in the nanomolar and makes it difficult for granulocytes to accumulate in the range) being specifically involved in the process of infection region. Similarly, in diabetic foot infection a poor vasculature without undesirable expression of targets in non-infected of distal toes has been described, thus migration of leukocytes tissues. can be impaired in soft tissue infections but still present when Furthermore, it is generally accepted that anti-G-mAbs lo- bone is infected. This different trend between soft tissue in- calize in infectious foci by two pathways: (a) in-vivo targeting fection and osteomyelitis has been reported only for diabetic of chemotactically activated granulocytes and (b) non-specific foot infections and can allow differentiation of soft tissue in- extravasation due to the locally enhanced vascular permeabil- fections from osteomyelitis but not soft tissue infections from ity, the later allowing delayed targeting at 10–20% ID. sterile inflammation [14]. Monoclonal antibodies visualize infectious foci in patients In-labeled WBC do not accumulate in the normal bowel. with a sensitivity between 80 and 90%, are very useful in the Intestinal activity is always abnormal and should be seen in evaluation of bone prosthetic infections (and in this case a com- antibiotic-associated colitis, pseudomembranous colitis, infec- bination with 3-phase bone scan is highly recommended) as well tious colitis, IBD, ischemic colitis or gastrointestinal bleeding. as of soft tissue infections such as vascular graft infection, pros- WBC do not usually accumulate in healing surgical thetic heart valve infection and inflammatory bowel disease wounds and their presence in these sites indicates a soft- [80–83], although these agents appear to be somewhat less accu- tissue infection. When the wound is very close to the bone rate than labeled leukocytes. Pulmonary infections—with the ex- surface (as in feet, tibia, skull, etc.) it might be difficult to ceptionoflungabscesses—are not easily visualized. Peripheral discriminate between soft tissue involvement alone or bone bone infections can be adequately visualized, but the sensitivity involvement too. Since OM is always much more clinically decreases if the focus is located closer to the spine [84]. relevant than a soft tissue infection, a differential diagnosis The major disadvantages of the murine monoclonal anti- must be made and SPECT/CT acquisitions may help in this bodies are that they are registered in Europe only for osteo- evaluation. myelitis diagnosis and that they may induce formation of hu- There are, however, certain exceptions to the rule. man anti-mouse antibodies (HAMA), which can result in al- Granulating wounds that heal by secondary intention can ap- tered biodistribution of subsequent injections [84]. pear as areas of intense uptake on WBC images even in the Colorimetric kit tests for rapid measurements of HAMA, how- absence of infection. Examples include stomas (e.g. tracheos- ever, are now commercially available and very easy to use tomy, ileostomy, feeding gastrostomy, etc.) and skin grafts. giving a result in less than 5 min. Vascular access lines, dialysis catheters and even lumbar punctures can all produce false-positive results and therefore Report of scintigraphic findings the importance of knowledge of the clinical history. A possible cause of non-infective accumulation of WBC in The final report of the study should be divided into five parts: the bone is the Paget disease. identification, clinical question, procedure description, report With complete and fragmented mAbs some differences in text and conclusions. physiological uptake should always be taken into consider- 99m ation: complete Tc-anti-NCA-95 antibody scans show in- & Identification: this includes the patient identification, the tense uptake in bone marrow, spleen > liver already 1–4 h p.i., institution where the scintigraphy was performed, the date whereas both kidneys are shown only slightly. Non-specific of scintigraphy, the type of scintigraphy, the name of ra- bowel activity is regularly seen after 20–24 h p.i. due to the diopharmaceutical and the activity administered to patient beginning of radiolabel instability. (MBq), and any other specification required by national 99m With Tc-anti-NCA-90 (Fab’) antibodies, bone marrow regulations, e.g. the name of the radiographer performing the study. is shown in a much lower degree as compared with complete Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 1829 Open Access This article is distributed under the terms of the Creative & Clinical question: this includes the clinical question and Commons Attribution 4.0 International License (http:// brief clinical history of the patient. Current treatment with creativecommons.org/licenses/by/4.0/), which permits unrestricted use, antibiotics or other interfering drugs should be reported. distribution, and reproduction in any medium, provided you give appro- & Procedure description: this includes the description of priate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. instrumentation used, the administration method of the radiopharmaceutical and the acquisition protocol. The use of SOPs should be mentioned as well as the European Guidelines for labelling, image acquisition and interpretation. References & Report text: this includes the description of qualitative and/ or semi-quantitative analysis. The qualitative analysis should 1. Signore A, Quintero AM. Diagnostic imaging of infections and inflammatory diseases: a multi-disciplinary approach. New York: describe the presence/absence of radiopharmaceutical Wiley; 2013. uptake, the site and size of uptake, and the intensity of up- 2. Lazzeri E, Signore A, Erba PA, Prandini N, Versari A, D’Errico G, take, preferably supported by semi-quantitative data. The et al. Radionuclide imaging of infection and inflammation. A pic- possible presence of factors that may have limited the sensi- torial case-based atlas. Italia: Springer-Verlag; 2013. tivity and specificity of the study, such as the presence of 3. Annovazzi A, Bagni B, Burroni L, D’Alessandria C, Signore A. Nuclear medicine imaging of inflammatory/infective disorders of motion artifacts, should be described. the abdomen. Nucl Med Commun. 2005;26:657–64. & Conclusions: This is the clear and conclusive answer to 4. Prandini N, Lazzeri E, Rossi B, Erba P, Parisella MG, Signore A. the clinical question. It can also suggest other diagnostic Nuclear medicine imaging of bone infections. Nucl Med Commun. procedures to be performed to confirm or exclude the di- 2006;27:633–44. agnosis made. The anatomical structures involved, as well 5. Cascini GL, De Palma D, Matteucci F, Biggi A, Rambaldi PF, Signore A, et al. Fever of unknown origin, infection of subcutane- as the presence, extent and the intensity of the infectious ous devices, brain abscesses and endocarditis. Nucl Med Commun. process have to be specified. At the end of the conclusions 2006;27:213–22. the name and surname of the Nuclear Medicine Physician 6. Capriotti G, Chianelli M, Signore A. Nuclear medicine imaging of reporting the study and of the technician performing the diabetic foot infection: results of meta-analysis. Nucl Med Commun. 2006;27:757–64. scan have to be clearly stated. 7. de Vries EF, Roca M, Jamar F, Israel O, Signore A. Guidelines for the labelling of leucocytes with (99m)Tc-HMPAO. Inflammation/ Acknowledgments The EANM Committee on Infection/Inflammation infection Taskgroup of the European Association of Nuclear Imaging would like to thank the following colleagues: Riddhika Medicine. Eur J Nucl Med Mol Imaging. 2010;37(4):842–8. Chakravartty, Paola Erba, Andor Glaudemans, Chiara Lauri, Olivier (Erratum in: Eur J Nucl Med Mol Imaging. 2010; 37(6):1235) Gheysens, Stephan Gratz, Napoleone Prandini and Francois Rouzet, 8. Roca M, de Vries EF, Jamar F, Israel O, Signore A. Guidelines for and for useful discussion and contribution to these guidelines. the labelling of leucocytes with (111)in-oxine. Inflammation/ The guidelines were brought to the attention of all other EANM infection Taskgroup of the European Association of Nuclear Committees and to the National Societies of Nuclear Medicine. The com- Medicine. Eur J Nucl Med Mol Imaging. 2010;37(4):835–41. ments and suggestions from the Pediatric, Oncology, Radiopharmacy and (Erratum in: Eur J Nucl Med Mol Imaging. 2010; 37(6):1234) the Physics Committee and from the Belgian, Italian and Finnish National 9. Signore A, Glaudemans AWJM, Malviya G, Lazzeri E, Prandini N, Societies are highly appreciated and have been considered for this Viglietti AL, et al. Development and testing of a new disposable Guideline. The publication of this article was supported by funds of the sterile device for labelling white blood cells. Q J Nucl Med Mol European Association of Nuclear Medicine (EANM). Imaging. 2012;56(4):400–8. 10. Locher JT, Seybold K, Andres RJ, Schubiger PA, Mach JP, Compliance with ethical standards Buchegger F. Imaging of inflammatory and infectious lesions after injection of radioiodinated monoclonal antigranulocyte antibodies. Disclaimer The European Association of Nuclear Medicine (EANM) Nucl Med Commun. 1986;7:659–70. has written and approved guidelines to promote the use of nuclear med- 11. Becker W, Bair J, Behr T, Repp R, Streckenbach H, Beck H, et al. icine procedures of high quality. The guidelines should not be deemed Detection of soft-tissue infections and osteomyelitis using a inclusive of all proper procedures and exclusive of other procedures rea- technetium-99m-labeled anti-granulocyte monoclonal antibody sonably directed to obtaining the same results. fragment. J Nucl Med. 1994;35(9):1436–43. The facilities in a specialized practice setting may be different from 12. Gratz S, Reize P, Kemke B, Kampen WU, Lusteri M, Hoffken H. those in a more general setting. Resources available to care for patients, Targeting of osteomyelitis with IgG and Fab’ monoclonal antibod- legislation and local regulations may vary greatly from one European ies labeled with [99mTc]: kinetic evaluations. Q J Nucl Med Mol country or one medical facility to another. For these reasons, these guide- Imaging. 2014;60:413–23. lines cannot be rigidly applied. 13. Palestro CJ, Mehta HH, Patel M, Freeman SJ, Harrington WN, Tomas MB, et al. Marrow versus infection in the Charcot joint: Conflict of interest All authors declare that they have no conflict of indium-111 leukocyte and technetium-99msulfur colloid scintigra- interest. phy. J Nucl Med. 1998;39:346–50. 14. Familiari D, Glaudemans AW, Vitale V, Prosperi D, Bagni O, Lenza Ethical approval This article does not contain any studies with human A, et al. Can sequential 18F-FDG PET/CT replace WBC imaging in participants or animals performed by any of the authors. the diabetic foot? J Nucl Med. 2011;52(7):1012–9. 1830 Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 15. Israel O, Sconfienza LM, Lipsky BA. Diagnosing diabetic foot 31. Panes J, Bouhnik Y, Reinisch W, Stoker J, Taylor SA, Baumgart DC, et al. Imaging techniques for assessment of inflammatory bow- infection: the role of imaging and a proposed flow chart for assess- ment. Q J Nucl Med Mol Imaging. 2014;58:33–45. el disease: joint ECCO and ESGAR evidence-based consensus guidelines. J Crohn’s Colitis. 2013;7(7):556–85. 16. Palestro CJ, Love C. Radionuclide imaging of musculoskeletal in- 32. Martín Comín J, Rodríguez Gasén A, Van de Wiele C. Nuclear fection: conventional agents. Semin Musculoskelet Radiol. medicine imaging of infections and inflammatory diseases of the 2007;11:335–52. abdomen. In: Signore A, Quintero AM, editors. Diagnostic imaging 17. Sonmezoglu K, Sonmezoglu M, Halac M, Akgün I, Türkmen C, of infections and inflammatory diseases: a multi-disciplinary ap- Onsel C, et al. Usefulness of 99mTc-ciprofloxacin (infecton) scan in proach. New York: Wiley; 2013. p. 216–40. diagnosis of chronic orthopedic infections: comparative study with 33. Signore A. Nuclear medicine imaging of abdominal infections and 99mTc-HMPAO leukocyte scintigraphy. J Nucl Med. 2001;42(4): inflammation. In: Lazzeri E, Signore A, Erba PA, Prandini N, 567–74. Versari A, D’Errico G, Mariani G, editors. Radionuclide imaging 18. Palestro CJ, Love C, Tronco GG, Tomas MB, Rini JN. Combined of infection and inflammation. A pictorial case-based atlas. Italia: labeled leukocyte and technetium-99m sulfur colloid marrow im- Springer-Verlag; 2013. p. 229–52. aging for diagnosing musculoskeletal infection: principles, tech- 34. Durack DT. Fever of unknown origin. In: Mackoviac PA, editor. nique, interpretation, indications and limitations. Radiographics. Fever. Basic mechanisms and management. 2nd ed. Philadelphia: 2006;26:859–70. Lippincott-Raven Pbl; 1997. p. 237–49. 19. Ballani NS, Al-Huda FA, Khan HA, Al-Mohannadi S, Mahmood H, 35. Peters AM. Nuclear medicine imaging in fever of unknown origin. Al-Enezi F. The value of quantitative uptake of (99m)Tc-MDP and Q J Nucl Med. 1999;43(1):61–73. (99m)Tc-HMPAO white blood cells in detecting osteomyelitis in vio- 36. Mourad O, Palda V, Detsky AS. A comprehensive evidence-based lated peripheral bones. J Nucl Med Technol. 2007;35(2):91–5. approach to fever of unknown origin. Arch Intern Med. 20. Jutte P, Lazzeri E, Sconfienza LM, Cassar-Pullicino V, Trampuz A, 2003;163(5):545–51. Petrosillo N, et al. Diagnostic flowcharts in osteomyelitis, 37. Xavier Hanin F, Jamar F. Nuclear medicine imaging of fever of spondylodiscitis and prosthetic joint infection. Q J Nucl Med Mol unknown origin. In: Signore A, Quintero AM, editors. Diagnostic Imaging. 2014;58:2–19. imaging of infections and inflammatory diseases: a multi- 21. van der Bruggen W, Bleeker-Rovers CP, Boerman OC, Gotthardt disciplinary approach. New York: Wiley; 2013. p. 273–90. M, Oyen WJG. PET and SPECT in osteomyelitis and prosthetic 38. Seshadri N, Solanki CK, Balan K. Utility of 111In-labeelled leuko- bone and joint infections: a systematic review. Semin Nucl Med. cyte scintigraphy in patients with fever of unknown origin in an era 2010;40:3–15. of changing disease spectrum and investigational techniques. Nucl 22. Palestro CJ. Nuclear medicine imaging of osteomyelitis: white Med Commun. 2008;29:277–82. blood cell, monoclonal antibody, or bacterial imaging? In: 39. Ascher NL, Ahrenholz DH, Simmons RL, Weiblen B, Gomez L, Signore A, Quintero AM, editors. Diagnostic imaging of infections Forstrom LA, et al. Indium-111 autologous tagged leukocytes in the and inflammatory diseases: a multi-disciplinary approach. New diagnosis of intraperitoneal sepsis. Arch Surg. 1979;114:386–92. York: Wiley; 2013. p. 168–86. 40. Coleman RE, Black RE, Welch OM, Maxwell JG. Indium-ill la- 23. Lazzeri E, Erba PA, Sollini M, Mariani G. Nuclear medicine imag- beled leukocytes in the evaluation of suspected abdominal abscess- ing of spondylodiscitis: the emerging role of PET. In: Signore A, es. Am J Surg. 1980;139:99–104. Quintero AM, editors. Diagnostic imaging of infections and inflam- 41. Morales KB. Nuclear medicine imaging of soft tissue infections. In: matory diseases: a multi-disciplinary approach. New York: Wiley; Signore A, Quintero AM, editors. Diagnostic imaging of infections 2013. p. 187–98. and inflammatory diseases: a multi-disciplinary approach. New 24. Fuster D, Tomás X, Mayoral M, Soriano A, Manchón F, Cardenal York: Wiley; 2013. p. 199–215. C, et al. Prospective comparison of whole-body (18)F-FDG PET/ 42. Palestro CJ. Love C, TroncoGG, Tomas MB. Role of radionuclide CT and MRI of the spine in the diagnosis of haematogenous imaging in the diagnosis of postoperative infection. Radiographics. spondylodiscitis. Eur J Nucl Med Mol Imaging. 2015;42(2):264– 2000;20:1649–60. 43. Borst U, Becker W, Maisch B, Börner W, Kochsiek K. Indium-111 25. Hungenbach S, Delank KS, Dietlein M, Eysel P, Drzezga A, or Tc-99m-HMPAO marked granulocytes as specific markers of Schmidt MC. 18F-fluorodeoxyglucose uptake pattern in patients florid stage endocarditis–results comparing clinical, histological with suspected spondylodiscitis. Nucl Med Commun. and scintigraphic findings in 30 patients with suspected endocardi- 2013;34(11):1068–74. tis. Z Kardiol. 1992;81(8):432–7. 26. Jamar F, Buscombe J, Chiti A, Christian PE, Delbeke D, Donohoe 44. Campeau RJ, Ingram C. Perivalvular abscess complicating infec- KJ, et al. EANM/SNMMI guideline for 18F-FDG use in inflamma- tive endocarditis: complementary role of echocardiography and tion and infection. J Nucl Med. 2013;54(4):647–58. indium-111-labeled leukocytes. ClinNucl Med. 1998;23(9):582–4. 27. Mulamba L, Ferrant A, Leners N, de Nayer P, Rombouts JJ, Vincent 45. Morguet AJ, Munz DL, Ivancević V, Werner GS, Sandrock D, A. Indium-111 leucocyte scanning in the evaluation of painful hip Bökemeier M, et al. Immunoscintigraphy using technetium-99m- arthroplasty. Acta Orthop Scand. 1983;54(5):695–7. labeled anti-NCA-95 antigranulocyte antibodies as an adjunct to 28. Palestro CJ, Kim CK, Swyer AJ, Capozzi JD, Solomon RW, echocardiography in subacute infective endocarditis. J Am Coll Goldsmith SJ. Total hip arthroplasty: periprosthetic In labeled Cardiol. 1994;23(5):1171–8. 99m leukocyte activity and complementary Tc sulfur colloid imaging 46. Erba P, Conti U, Lazzeri E, Sollini M, Doria R, De Tommasi SM, et 99m in suspected infection. J Nucl Med. 1990;31:1950–5. al. Added value of Tc-HMPAO labelled leukocytes SPECT/CT 29. Palestro CJ, Swyer AJ, Kim CK, Goldsmith SJ. Infected knee pros- imaging in the characterization and management of patient with thesis: diagnosis with in-111-leukocyte, Tc-99m-sulfur colloid and infectious endocarditis. J Nucl Med. 2012;53(8):1235–43. Tc-99m-MDP imaging. Radiology. 1991;179:645–8. 47. Iung B, Erba PA, Petrosillo N, Lazzeri E. Common diagnostic 30. Love C, Marwin SE, Tomas MB, Krauss ES, Tronco GG, Bhargava flowcharts in infective endocarditis. Q J Nucl Med Mol Imaging. KK, et al. Diagnosing infection in the failed joint replacement: a 2014;58:55–65. comparison of coincidence detection fluorine-18 FDG and indium- 48. Fiorani P, Speziale F, Rizzo L, De Santis F, Massimi GJ, Taurino M, 111-labelled leukocyte/technetium-99m-sulfur colloid marrow im- et al. Detection of aortic graft infection with leukocytes labeled with aging. J Nucl Med. 2004;45:1864–71. technetium 99m-hexametazime. J Vasc Surg. 1993;17:87–96. Eur J Nucl Med Mol Imaging (2018) 45:1816–1831 1831 49. Krznaric E, Nevelsteen A, Van Hoe L, de Roo M, Schiepers C, 67. Sampson CB. Complications and difficulties in radiolabelling 99 m blood cells: a review. Nucl Med Commun. 1996;17(8):648–58. Verbuggen A, et al. Diagnostic value of Tc -d,l-HMPAO-labelled leukocyte scintigraphy in the detection of vascular graft infections. 68. Sampson CB. Interference of patient medication in the Nucl Med Commun. 1994;15:953–60. radiolabelling of white blood cells: un update. Nucl Med 50. Prats E, Banzo J, Abós MD, Garcia-Lopex F, Escalera T, Garcia- Commun. 1998;19(6):529–33. Miralles M, et al. Diagnosis of prosthetic vascular graft infection by 69. Glaudemans AW, de Vries EF, Vermeulen LE, Slart RH, Dierckx technetium-99m-HMPAO-labeled leukocytes. J Nucl Med. RA, Signore A. A large retrospective single-Centre study to define 1994;35:1303–7. the best image acquisition protocols and interpretation criteria for 99m 51. Liberatore M, Iurilli AP, Ponzo F, Prosperi D, Santini C, Baiocchi P, white blood cell scintigraphy with Tc-HMPAO-labelled et al. Aortofemoral graft infection: the usefulness of 99m-Tc- leucocytes in musculoskeletal infections. Eur J Nucl Med Mol HMPAO-labelled leukocyte scan. Eur J VascEndovasc Surg. Imaging. 2013;40(11):1760–9. 1997;14(Suppl A):27–9. 70. Erba PA, Glaudemans AW, Veltman NC, Sollini M, Pacilio M, Galli 52. Setacci C, Müller-Hülsbeck S, Jamar F. Common diagnostic flow- F, et al. Image acquisition and interpretation criteria for (99m)Tc- charts in vascular and endovascular surgery. Q J Nucl Med Mol HMPAO-labelled white blood cell scintigraphy: results of a Imaging. 2014;58:46–54. multicentre study. Eur J Nucl Med Mol Imaging. 2014;41(4):615–23. 53. Israel O. Nuclear medicine imaging of vascular graft infection: the 71. Grippaudo FR, Pacilio M, Di Girolamo M, Dierckx RA, Signore A. added role of hybrid imaging. In: Signore A, Quintero AM, editors. Radiolabelled white blood cell scintigraphy in the work-up of der- Diagnostic imaging of infections and inflammatory diseases: a mal filler complications. Eur J Nucl Med Mol Imaging. 2013;40(3): multi-disciplinary approach. New York: Wiley; 2013. p. 241–54. 418–25. 54. Love C, Opoku-Agyemang P, Tomas MB, Pugliese PV, Bhargava 72. Rubello D, Casara D, Maran A, Avogaro A, Tiengo A, Muzzio PC. KK, Palestro CJ. Pulmonary activity on labeled leukocyte images: Role of anti-granulocyte Fab’ fragment antibody scintigraphy physiologic, pathologic, and imaging correlations. Radiographics. (LeukoScan) in evaluating bone infection: acquisition protocol, in- 2002;22:1385–93. terpretation criteria and clinical results. Nucl Med Commun. 55. Palestro C, Swyer AJ, Kim CK, Muzinic M, Goldsmith SJ. Role of 2004;25(1):39–47. 111In-labeled leukocyte scintigraphy in the diagnosis of intracere- 73. Rubello D, Rampin L, Banti E, Massaro A, Cittadin S, Cattelan bral lesions. Clin Nucl Med. 1991;16:305–8. AM, et al. Diagnosis of infected total knee arthroplasty with anti- 56. Kim DG, Lee JL, Lee DS, Lee MC, Choi KS, Han DH. 99mTc- granulocyte scintigraphy: the importance of a dual-time acquisition HMPAO labeled leukocyte SPECT in intracranial lesions. Surg protocol. Nucl Med Commun. 2008;29(4):331–5. Neurol. 1995;44:338–45. 74. Skehan SJ, White JF, Evans JW, Parry-Jones DR, Solanki CK, 99m 57. Grimstad IA, Hirschberg H, Rootwelt K. 99mTc- Ballinger JR, et al. Mechanism of accumulation of Tc- hexamethylpropylene amine oxime leucocyte scintigraphy and sulesomab in inflammation. J Nucl Med. 2003;44(1):11–8. C-reactive protein levels in the differential diagnosis of brain ab- 75. Peters AM, Ballinger JR. Timing for evaluating Bspecific^ binding 99m scesses. J Neurosurg. 1992;77:732–6. of Tc-sulesomab in peripheral bone infection. J Nucl Med. 58. Spinelli F, Sara R, Milella M, Ruffini L, Sterzi R, Causarano IR, et 2005;46(2):382–3. al. Technetium-99m hexamethylpropylene amine oxime leucocyte 76. Pelosi E, Baiocco C, Pennone M, Migliaretti G, Varetto T, Maiello scintigraphy in the differential diagnosis of cerebral abscesses. Eur J A, et al. 99mTc-HMPAO-leukocyte scintigraphy in patients with Nucl Med. 2000;27:46–9. symptomatic total hip or knee arthroplasty: improved diagnostic 59. Medina M, Viglietti AL, Gozzoli L, Lucano A, Ravasi L, Lucignani accuracy by means of semiquantitative evaluation. J Nucl Med. G, et al. Indium-111 labelled white blood cell scintigraphy in cranial 2004;45(3):438–44. and spinal septic lesions. Eur J Nucl Med. 2000;27:1473–80. 77. Wang SJ, Kao CH, Chen DU, Lin MS, Yeh SH, Lan JL. 60. Goethals I, Dierckx R, Van Laere K, Van de Wiele C, Signore A. Quantitative 99mTc-HMPAO white blood cells and 67Ga scanning The role of nuclear medicine imaging in routine assesment of in- in rheumatoid arthritis. Nucl Med Commun. 1991;12(6):551–8. fections brain pathology. Nucl Med Commun. 2002;23:819–26. 78. MacSweeney JE, Peters AM, Lavender JP. Indium labelled leuco- 61. Signore A, Biggi A. Nuclear medicine imaging of infections and cyte scanning in pyrexia of unknown origin. ClinRadiol. 1990 inflammation of central nervous system, head and neck structures. Dec;42(6):414–7. 99m In: Lazzeri E, Sigmore A, Erba PA, Prandini N, Versari A, D’Errico 79. Gutfilen B, Lopes de Souza SA, Martins FP, et al. Use of Tc- G, Mariani G, editors. Radionuclide imaging of infection and in- mononuclear leukocyte scintigraphy in nosocomial fever. Acta flammation. Italia: Springer-Verlag; 2013. p. 165–80. Radiol. 2006;47(7):699–704. 62. Sandrock D, Verheggen R, Helwig AT, Munz DL, Makakis E, 80. Becker W, Bair J, Behr T, et al. Detection of soft-tissue infections Emrich D. Immunoscintigraphy in the detection of brain abscesses. and osteomyelitis using a technetium-99m labelled anti granulocyte Nucl Med Commun. 1996;17:311–6. monoclonal antibody fragment. J Nucl Med. 1994;35:1436–43. 63. Schmidt KG, Rasmussen JW, Frederiksen PB, Kock-Jensen C, 81. Gratz S, Schipper ML, Dörner J, et al. LeukoScan for imaging Pedersen NT. Indium-ill-granulocyte scintigraphy in brain abscess infection in different clinical settings: a retrospective evaluation diagnosis: limitations and pitfalls. J Nucl Med. 1990;31:1121–7. and extended review of the literature. Clin Nucl Med. 2003;4: 64. Fineman D, Palestro CJ, Kim CK, Needle LB, Vallabhajosula S, 267–76. Solomon RW, et al. Detection of abnormalities in febrile AIDS 82. Papos M, Nagy F, Narai G,etal. Anti-granulocyte patients with In-111-labeled leukocyte and GA-67 scintigraphy. immunoscintigraphy and [99mTc]hexamethylpropyleneamine-ox- Radiology. 1989;170:677–80. ime-labeled leukocyte scintigraphy in inflammatory bowel disease. 65. Palestro CJ, Goldsmith SJ. The use of gallium and labeled leuko- Dig Dis Sci. 1996;41:412–20. cyte scintigraphy in the AIDS patient. Q J Nucl Med. 1995;39:221– 83. Gratz S, Braun HG, Behr TM, et al. Photopenia in chronic vertebral 30. osteomyelitis with technetium - 99mTc-antigranulocyte antibody 66. Sathekge M, Van de Wiele C, Signore A. Nuclear medicine imaging (BW 250/183). J Nucl Med. 1997;38(2):211–6. of tuberculosis and human immunodeficiency virus. In: Signore A, 84. Meller J, Liersch T, Oezerden MM, Sahlmann C-O, Meller B. Quintero AM, editors. Diagnostic imaging of infections and inflam- Targeting NCA-95 and other granulocytes antigen and receptors matory diseases: a multi-disciplinary approach. New York: Wiley; with radiolabeled monoclonal antibodies (Mabs). Q J Nucl Med 2013. p. 255–72. Mol Imaging. 2010;54:582–98.

Journal

European Journal of Nuclear Medicine and Molecular ImagingSpringer Journals

Published: May 31, 2018

References

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