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World Journal of Nuclear Medicine, Volume 4, Number 2, April 2005
Nuclear Medicine imaging of infection and inflammation
P...
World Journal of Nuclear Medicine, Volume 4, Number 2, April 2005
Specificity drops to about 35% in patients with
complica...
World Journal of Nuclear Medicine, Volume 4, Number 2, April 2005
Diabeticfoot
In patients with diabetes, osteomyelitis of...
World Journal of Nuclear Medicine, Volume 4, Number 2, April 2005
seem to improve specificity significantly (19). Combined...
World Journal of Nuclear Medicine, Volume 4, Number 2, April 2005
abnormality. The overall reported accuracy of a Tc-99m
M...
World Journal of Nuclear Medicine, Volume 4, Number 2, April 2005
prosthesis(34,35).
Reports suggest that F-18 FDG is usef...
World Journal of Nuclear Medicine, Volume 4, Number 2, April 2005
On a 3-phase bone scan the inflamed joint will demonstra...
World Journal of Nuclear Medicine, Volume 4, Number 2, April 2005
labeled leukocytes, Tc-99m/ In-111 HIG and
antigranulocy...
References
1. Wegener WA, Alavi A. Diagnostic imaging of
musculoskeletal infection. Roentgenography; gallium,
indium-label...
World Journal of Nuclear Medicine, Volume 4, Number 2, April 2005
infections of the locomotor system with indium-111-
labe...
World Journal of Nuclear Medicine, Volume 4, Number 2, April 2005
tropolonate labelled granulocytes. Nucl Med Commun.
1988...
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  1. 1. World Journal of Nuclear Medicine, Volume 4, Number 2, April 2005 Nuclear Medicine imaging of infection and inflammation Part 3: Clinical applications Gnanasegaran G, Croasdale J, Buscombe JR Department of Nuclear Medicine, Royal Free Hospital, London NW3 2QG, U.K Correspondence: Dr. J.R.Buscombe MD Consultant-Nuclear Medicine Royal Free Hospital London NW3 2QG, U.K Email: j.buscombe@rfc.ucl.ac.uk Abstract Key words: Infection imaging, osteomyelitis, diabetic foot, FeverofUnknownOrigin,HIV Introduction Prompt localization of infection sites is essential for initiating appropriate therapeutic measures. There have been major advances in the management of patients suffering from infective and/or inflammatory disorders as a result of introduction of newer drugs with high sensitivity and specificity. However diagnosis of infection / inflammation still remains a major clinical problem. Although the typical signs of infection and inflammation are useful in localizing the pathology at superficial sites, infection and inflammation of internal structures are often difficult to localize without the aid of imaging procedures. Radionuclide imaging is an important diagnostic tool for the evaluation of patho-physiological processes of infection and inflammation. A spectrum of radiopharmaceuticals and a number of imaging protocols have been used in clinical practice. However every method differs in its potential to gather information at the cellular and molecular level. This review addresses some of the applications of radionuclide infection imaging procedures in musculoskeletal system, lymphatic system, in immuno- compromised patients and in patients suffering from fever of unknown origin. In the previous article published in the October 2004 issue of WJNM, we addressed the application of radionuclide infection imaging procedures in central nervous, respiratory, cardiovascular, Gastrointestinal, hepatic, hepatobiliary and genitor-urinarty systems. This part of the review will cover musculo-skeletal and lymphatic systems; as well as infection imaging in immuno-compromised patientsandinpatientswithfeverofunknownorigin. Musculoskeletal system Bone infections are complex and may result in significant WorldJ NucMed2005;4:127-137 disability.This may be of particular concern in patients with diabetes where infections may be more severe and difficult to treat. The diagnosis of musculoskeletal infection/inflammation is based on clinical presentation, tissue culture, laboratory investigations and organ imaging. Conventional radiography, ultrasound, magnetic resonance imaging (MRI), computed tomography (CT) and radionuclide imaging procedures are selectively used to aid in the diagnosi of infection and assessment of the extent of bone involvement (Table-1). The major diagnostic difficulty in diabetic patients is distinguishing bone infection from non-infectious neuropathic bony lesion (1). Chronic infections can lead to contiguous bone infection and these infections are potentially limb or life threatening. In general, imaging bone infection with nuclear medicine techniques is very sensitive either for whole body screening or local detection of acute or exacerbated chronic infection/inflammation. The organism most commonly responsible for heamatogenous osteomyelitis is S. Aureus. Group B streptococcal infection is seen more commonly in neonates (1, 2). Imaging techniques for the diagnosis of osteomyelitis have a wide range of sensitivity, specificity and positive predictive values. Radiographic changes in early osteomyelitis are difficult to interpret and lag at least 2 weeks behind the time when scintigraphy becomes positive.About 90% of cases do not manifest the disease on planar X-ray until 3 to 4 weeks after the infective process has set in (1). CT may show increased density within the marrow, but this may be difficult to appreciate. The overall sensitivity and specificity of MRI for the detection of acute osteomyelitis ranges from 92-100 %, and 89-100% respectively (1, 3-9). Common nuclear medicine techniques for the diagnosis of osteomyelitis include three or four-phase bone scans, Gallium-67 scintigraphy, radiolabeled white cell studies and leukoscan. Tc-99m MDPbone scan is highly sensitive for the diagnosis of osteomyelitis and detects osteomyelitis 1 to 2 weeks before radiological changes are manifested (1) (Table 2). Three-phase bone imaging includes dynamic and static bone imaging (arterial, soft-tissue and cortical phases) is useful. In osteomyelitis, all three phases demonstrate increased activity with the third phase showing focal uptake in the area of osteomyelitis (1). The 3-phase bone scan has a reported sensitivity of 90-100% and a specificity of 70-95% for identification of osteomyelitis in non-violated bone. Osteomyelitis 127 Review
  2. 2. World Journal of Nuclear Medicine, Volume 4, Number 2, April 2005 Specificity drops to about 35% in patients with complicating bone conditions such as recent fracture, trauma or surgery (1, 10). Gallium-67 scan can be positive as early as 4 hours after the onset of infection, and it is usually positive by 24 hours (10). Gallium imaging lacks some specificity as there can be increased uptake in metabolically active bone and bone marrow. A normal Gallium scan virtually excludes the diagnosis of acute osteomyelitis with a high degree of certainty (negative predictive value 90-100%) (11). In-111 labeled leukocyte imaging has a higher sensitivity and specificity for the diagnosis of acute osteomyelitis than combined bone/Gallium imaging (1). Schauwecker (12) reported In- 111 labeled leukocyte imaging to have a sensitivity of 90-95% in acute osteomyelitis for all bones in the body (overall sensitivity from various studies ranges from 80 to 100%) (12). In-111 labeled leukocyte imaging is very sensitive (except in some cases of chronic osteomyelitis), specific, and the method of choice for diagnosing and localizing distal appendicular skeletal osteomyelitis (13). Tc-99m labeled monoclonal antibody-Fab' fragments (LeukoScan) is useful for detecting osteomyelitis. It is reported to have high sensitivity and specificity (14) (Figure 1). The advantage of LeukoScan is that a result can be obtained in few hours (1 to 2 hours) after injection (14) and is useful in the detection of spinal infections and infections at sites with normal bone marrow (15). Tc-99m nanocolloids have been used in patients with osteomyelitis with reported sensitivity ranging from 87 to 95% and specificity between 77 and 100% (16). Indications Radiopharmaceuticals Musculoskeletal system (A-E, J, K, M, R) Osteomyelitis Diabetic foot Sternal infection Prosthesis infection Disease activity in rheumatoid arthritis Lymphatic system (D, I) Lymph node disease in hila, mediastinum Sarcoidosis Mycobacterial Infections Miscellaneous Pyrexia/ fever of unknown (FUO/FUO) (B, D, I, J) 1.Intra-thoracic disease Bronchiectasis Malignacies-lypmphoma Infectious and non-infectious granulomatous disease-Tuberculosis, sarcoidosis Pulmonary vasculitis 2.Intra-abdominal disease Intraabdominal sepsis-subphrenic, intra-hepatic, intra-splenic , peri-renal, Free septic fluid in the peritoneal cavity. 3.Soft tissue sepsis 4.Post operative fever 5.Renal disease Non-functioning allograft Infected current or old access grafts Infection of catheter tunnel Immunodeficiency syndrome / Human immunodeficiency virus (HIV) infection (D, F, J) Vascular graft rejection (B, C, D, I) A. Tc-99m MDP B. Tc-99m HMPAO labeled leukocytes C. In-111 oxine labeled leukocytes D. Gallium-67 E. Tc-99m Infecton F. Tc-99m DTPA G. Tc-99m pyrophosphate H. In-111 antimyosin antibody I. F-18 flurodeoxyglucose (FDG) J. Tc-99m/In-111 HIG (human immunoglobin) K. Tc-99m Nanocolloid L. Tc-99m Colloids M. Tc-99m antigranulocyte antibody (Leukoscan) N. In-111 Tropolonate labeled leukocytes O. Tc-99m/In-111 Liposomes P. I-123 IL2 (Interleukin 2) (Lymphocytes) Q. Tc-99m IL8 (Interleukin 8) (Granulocytes) . R In-111 pentetreotide (Octreoscan) S .Tc-99m IDA (Iminodiacetic acid) T.Tc-99m DMSA(dimercaptosuccinic acid) U.Tc-99m HMPAO Table1. Indications of infection and inflammation imaging and radiopharmaceuticals 128 Gnanasegaran G, Croasdale J, Buscombe JR
  3. 3. World Journal of Nuclear Medicine, Volume 4, Number 2, April 2005 Diabeticfoot In patients with diabetes, osteomyelitis of the foot is a common and serious problem (17). Infections usually appear in foot ulcers, which are associated with neuropathy, vasculopathy, and various metabolic disturbances (18). Aetiologic agents are usually aerobic gram-positive cocci, but chronic or serious infections often contain gram- negative rods and anaerobes (18). Charcot's osteoarthropathy may also occur in the diabetic foot (19). It is important to distinguish this from other conditions, such as osteomyelitis (19) (Figure 2). Sella et al have reported that a three-phase bone scan alone is not specific enough to distinguish between Charcot's and osteomyelitis in the mid- foot (19). Additional four-phase scan or gallium does not Technique Advantages Drawbacks 30% to 50% loss of bone density must occur before a radiograph shows abnormality. It is often difficult to gauge the extent of infection. Sensitivity to detect osteomyelitis of the diabetic foot is low. Degenerative or Inflammatory arthritis and neuropathic joints generate false- positive results. Diagnosis of osteomyelitis is limited to the detection of soft tissue abnormalities around the bone. Differentiation of sequestra from osteoid osteomas may be problematic. Noninfectious hemorrhage, neoplasm, stress fracture, and/or radiation therapies have similar CT-detected increases in intramedullary density as infectious inflammation does. Scatter phenomenon, which occurs when metal is present in or near the area of bone infection. Not Cost-effective. High cost. Lack of universal availability. Imaging interference caused by metal implants, and lower resolution of calcified bone structures and the cortex. Differentiation of infection from Trauma, infarct, ischemia, or neoplastic process may be difficult. These may resemble osteomyelitis in MRI. High false-positive rates have occurred in patients with soft tissue infections such as the diabetic foot, decubitus ulcer infections, septic arthritis and non- infectious Inflammatory bone disease. False-negative bone scans occur and apparently do not correlate with the onset of disease, antibiotic therapy, causative organism, or radiographic changes. Least expensive Readily available. Non-invasive, inexpensive, easy-to-use and devoid of radiation. Evaluates soft tissues and presence of fluid accumulation next to prosthetic implants. Provides high spatial resolution images and explicit cortical bony details. Displays anatomic detail to view end- plate erosions and para-vertebral masses in vertebral osteomyelitis. Useful in guiding bone biopsy and detecting very small sequestra, cortical abnormalities, soft tissue extension, hyper attenuation and constriction of the medullary cavity, destruction of cortical bone, and new bone formation. MRI displays greater resolution for soft tissue abnormalities than CT scans or radiographs and greater anatomical detail than radionuclide scans. MRI is a useful modality for differentiating between bone and soft tissue infection. Extremely useful in patients with vertebral osteomyelitis and has a sensitivity of 96% and specificity of 92% Three-phase Tc-99m MDP scans are very sensitive in the detection of osteomyelitis, (sensitivity of 92% and specificity of 94% in non-violated bone) Least expensive Readily available. X-ray Ultrasound CT MRI Three-phase Tc-99m MDP bone scan Table 2. Imaging osteomyelitis (3-9) 129 Gnanasegaran G, Croasdale J, Buscombe JR
  4. 4. World Journal of Nuclear Medicine, Volume 4, Number 2, April 2005 seem to improve specificity significantly (19). Combined leukocyte scans and sulfur colloid marrow scans have been reported to improve the specificity and distinguish Charcot's from osteomyelitis. Sella et al have reported that, combined leukocyte scans and bone marrow imaging are the gold standard for evaluating the diabetic foot infection and distinguishing it from osteoarthropathy (19). However, other groups working in this area have not confirmed these finding. Although, X-ray is less sensitive than other imaging modalities it should be used as the initial diagnostic procedure in suspected osteomyelitis in the diabetic patients as it may show morphological changes, which may explain some of the nonspecific abnormalities on the radionuclide studies (20). Prosthesis infection Infection around hip and knee arthroplasties is a major problem in orthopaedic surgery (21). The presence of infection changes the management drastically (21). Generally, the causes for pain in hip prosthesis are mechanical and biological (21). The mechanical causes include the distal load transfer and the periprostheic bone resorption (21). The biological causes include aseptic loosening (polyethylene debris reaction) and septic loosening (infection) (21). Radionuclide imaging plays a very valuable role in detecting infection around hip and knee arthroplasties. The three-phase Tc-99m MDP bone scan has a high sensitivity but low specificity. However, a normal study is a strong indicator against prosthetic 130 Figure 1. Diabetic man with distal tibial osteomyelitis. SPECT bone scan shows abnormal intense focal radiotracer uptake in the distal end of left tibia (Left). On the other hand the 4 hour Tc-99m leukoscan SPECT (Right) shows concentra- tionof radiotraceratthesiteof infection(arrow),aswellasinthecorticalsequestrum(arrow) Figure2. Tc-99mHIGscaninapatientofdiabeteswithosteomyelitisofrightfoot.Pleasenoteintenseradiotraceruptakeinthelesion. Gnanasegaran G, Croasdale J, Buscombe JR
  5. 5. World Journal of Nuclear Medicine, Volume 4, Number 2, April 2005 abnormality. The overall reported accuracy of a Tc-99m MDP bone scan in the evaluation of a painful prosthetic joint is only about 50-70% (22).The reason for this could be because of variable patterns in the peri-prosthetic uptake. There are different types of prosthesis, which have not been studied in detail in terms of normal evolution of peri- prostheticuptakepatterns(23). Sequential bone and gallium imaging has also been used to evaluate painful joint prosthesis. The overall reported accuracy of this technique is about 70-80% (22) (Table 3). Gallium uptake in general is related to inflammation and not to infection. So this technique is not suited for differentiatinginfectionandinflammation(24). Radiolabelled leukocytes are useful for imaging the joint prosthesis.The sensitivity and specificity ofTc-99m/In-111 labeled leukocytes are reported to be high (Figure 3). The published results on the accuracy of radiolabelled leukocytes are variable. The interpretation of radiolabelled leukocyte images entails a comparison of uptake/activity in the region of interest to activity/uptake in some reference points. Increased activity compared to the reference point is interpreted as positive for infection (22-30). The combination of Tc-99m MDP with Tc-99m /In-111 labeled leukocytes improves the diagnostic efficacy (23, 31). Radiolabelled leukocytes may also accumulate in the bone marrow, which remains around any prosthesis, often presenting as small islands of activity, which could be mis- read as focal infection. This can be overcome by bone marrow imaging with sulphur colloid (22). Both radiolabeled leukocytes and sulphur colloid accumulate in the bone marrow, but only radiolabeled leukocytes accumulate at the site of infection (22). Therefore if the distribution of the two agents is congruent, infection is less likely than if it is non-congruent, with labeled white cells being present but no bone marrow activity on the marrow scan. The reported accuracy of combined leukocyte/marrow imaging is about 90% (22, 32). Orthopaedic infection can also be successfully imaged with Tc-99m antigranulocyte antibody Fab' fragments (Leukoscan). LeukoScan is reported to have a high sensitivity in diagnosing bone infection in patients with diabetic foot and joint prosthesis or other peripheral bone implants (33). In our experience SPECT improves both the visualization and localization of infection around the prosthetic knee. Current data also indicate that Tc-99m ciprofloxacin is a useful method for imaging hip prosthesis infection (34). Tc-99m ciprofloxacin imaging showed diagnostic sensitivity of 86% and a specificity of 78% for correctly classifying the presence of infection in patients with knee Diagnosis Gallium-67 Thallium-201 Pulmonary infection Positive Negative Kaposi's sarcoma Negative Positive Mycobacterial infection Strongly positive Weakly positive Table 4 . Patterns of uptake in lungs in patients with AIDS (60) 131 Tracers Sensitivity Specificity 67 Ga/bone 66 % 81% 99m Tc-nanocolloid 100% 82% 111 In-HIG 100% 100% 111 In-leukocyte/bone 88% 95% 111 In-leukocyte/marrow 100% 97% 99m Tc-leukocyte 97% 89% 99m Tc-LeukoScan 85% 77% 99m Tc-ciprofloxacin 92% 91% Table 3 Sensitivity and specificity of various radiopharmaceuticals in knee and hip prosthesis imaging (22,25-31,34,35) Gnanasegaran G, Croasdale J, Buscombe JR
  6. 6. World Journal of Nuclear Medicine, Volume 4, Number 2, April 2005 prosthesis(34,35). Reports suggest that F-18 FDG is useful in detecting infected joint prosthesis. However, in spite of high sensitivity, it cannot differentiate aseptic loosening from infection(22,36,37). Sternalinfection Sternal split for cardiac surgery (coronary artery bypass graft) is usually the cause of fever. The incidence of strenal infection ranges from 0.4% to 8-9% and with complications such as mediastinitis the mortality is reported to be high (23). It is important to distinguish superficial and deep- seated sternal wound infection (23). Radiolabelled leukocyte imaging is reported to be useful in these infections(23). Septicarthritis Septic arthritis is infection of a joint. It is commonly due to pyogenic organisms. Large joints such as the hip and knee are most usually involved (38). Radionuclide scans are reported to be of limited use in patients with septic arthritis (38). However, reports suggest that Gallium-67 and In-111 labeled scans can be used to localize the sites of infection (38). Although these scans are sensitive, it is difficult to delineate the joint structures. This could be improved by performing a SPECT study of the joint. In-111 labeled leukocyte scan is reported to be positive in 60% of cases (38). False-positive results occur in patients with synovitis secondarytoactiveosteoarthritis(38). Rheumatoid arthritis Rheumatoid arthritis is an autoimmune disease that causes chronic inflammation of the joints. Traditional method of monitoring the joint disease of patients with rheumatoid arthritis is x-rays. MRI has been found to be sensitive as an indicator of early rheumatoid joint destruction, but it is very expensive. Tc-99m MDP bone scans are very sensitive in detecting reactive bone oedema associated with osteoarthritis. Differentiation of a septic arthritis from a non-infectious synovial inflammation is not possible by scintigraphy. Tc-99m MDP will demonstrate increased tracer activity at the sites of inflammation. Gallium-67 and In-111 labeled leukocytes will also accumulate at these sitesofinflammation. Figure 4. A classical Ga-67 citrate scan in a patient suffering from sarcoidosis, anterior (left) and posterior (right) views showing lacrimal, nasal and parotid uptake (Panda sign), mediastinal and hilar lyphadanopathy (lambda sign). In addition there is also uptake in the groin lymph nodes. 132 Gnanasegaran G, Croasdale J, Buscombe JR
  7. 7. World Journal of Nuclear Medicine, Volume 4, Number 2, April 2005 On a 3-phase bone scan the inflamed joint will demonstrate diffusely increased flow and blood pool activity. Delayed images usually demonstrate increased activity within the bone on either side of the joint. However, Tc-99m MDP bone scan is of limited value in the evaluation of juvenile rheumatoid arthritis. The prominent uptake of tracer within the growth plates often obscures increased peri-articular traceruptake,especiallyinsmalljoints. Tc-99m polyclonal immunoglobulin-G has been shown to be a successful agent in the depiction of active inflammation in rheumatoid arthritis (RA). The detection rate of active joint inflammation with Tc-99m HIG is reported to be much higher than that with Tc-99m MDP (39). However, it is not the method that should be applied in all patients. Tc-99m IgG-scintigarphy is well suited for follow-up of patients under treatment with persistent complaints (40). Though Tc-99m Ciprofloxacin (Infecton) scintigraphy is reported to have good sensitivity and a high negative predictive value for the detection of bone and joint infection, it may not always discriminate between infected and aseptic osteoarticular diseases in symptomatic patients referred for surgery (41). Appelboom et al reported that Infectonscans could be an additional method of imagingthe inflammatory synovial process in arthritis (42). It is also reported that In-111 pentetreotide accumulates at the inflammatory sites and could be useful in imaging arthritis (43). Further studies are necessary. The use of PET scans with C-11 choline is reported to be a promising tracer for quantitative imaging of proliferative arthritis changes (44). But further evaluation is necessary and this technique is expensive. Vascular graft infection is a common and serious complication of reconstructive surgery. It is reported to occur in 2% of patients (45).The successful management of vascular graft infection depends on correct diagnosis and evaluation of the extent (46). Various radiopharmaceuticals are used in imaging vascular graft infections (Gallium- 67/Tc-99m HMPAO labeled leukocytes, In-111 oxine Vascular graft rejection/infection Figure 5. Tc-99m leukoscan in a patient with fever of unknown origin. Posterior view. Note a small area of increased focal uptake near the spleen, which turned out to be a psoas abscess. 133 Figure 6. Ga-67 citrate scan in a patient with AIDS and pneumocystis carinii pneumonia, showing intense lung uptake. Gnanasegaran G, Croasdale J, Buscombe JR
  8. 8. World Journal of Nuclear Medicine, Volume 4, Number 2, April 2005 labeled leukocytes, Tc-99m/ In-111 HIG and antigranulocyte monoclonal antibody). Delgado et al. reported that the radiolabeled leukocyte scan is more useful than Tc-99m HIG (47). According to Prats et al, Tc-99m HMPAO labeled leukocytes is the radiopharmaceutical of choice for the evaluation of vascular grafts. Tc-99m HMPAO labeled leukocytes have an overall sensitivity and specificity greater than 85-90% (45,48). The commonly advocated protocol is to image the vascular (Flow) phase, 5-minute, 30 minute, and 3 hour over the region of interest. Whole body images should also be acquired at 3 hours and occasionally 24-hour images are helpful (45,49-51). The common causes for false positive of Tc-99m HMPAO labeled leukocyte scans are perigraft haematoma, graft thrombosis, bleeding, pseudo aneurysms and scans performed in the first days after surgery (45,49-51). The major parts of the lymphatic system are the bone marrow, spleen, thymus, lymph nodes and the tonsils. Other organs like lungs, intestines, liver and skin also contain lymphatic tissue. The lymphatic system branches through most of the parts of the body; it can be involved in a wide range of conditions. Lymphadenopathy might be the result of an infection and swelling of the lymph nodes can be due to an infiltration of cancerous cells. Generalized lymphadenopathyusuallyindicatessystemicdisease. Lymph node disease Lymph node disease in hila of lungs and mediastinum may represent reactive changes due to infection within the lung or from other granulomatous disease (Sarcoid, Mycobacterial Infections) (52). Radionuclides like Gallium-67 and F-18 FDG can be used in the assessment of lymphadenopathy (Figure 4).Acombination of Gallium-67 and Thallium-201 is used to differentiate between the inflammatory and malignant nature of lymphadenopathy (52). Most recently work with F-18 FDG PET has suggested that this technique can also be used to monitor the progression of viral disease with both HIV and flu virus (53-55). Pyrexia of unknown origin is described as fever lasting at least 28 days with 7 days of in-patient investigations failing to find the causative agent. Gallium-67, In-111/Tc-99m labeled leukocytes and polyclonal HIG are the most commonly used agents for detection of FUO (30). Gallium-67 is reported to be the agent of choice in FUO and occult infection greater than 2 weeks (56). Gallium-67 is not used to make a diagnosis, but to localize the site, which can then be further investigated by conventional modalities like CT/MRI. Increased Gallium-67 uptake in seen in both infectious and inflammatory conditions (pyogenic abscess, tuberculosis, sarcoidosis and vasculitis). Diagnosing abdominal pathology with Gallium-67 could be difficult due to non- specific bowel activity. Lymphatic system Fever of unknown (FUO) In-111/Tc-99m labeled leukocytes are useful to identify occult infections. The probability of successful localization using a radiolabeled leukocyte scan is higher if the clinical scenario is pointing towards a pyogenic infection. Successful imaging with radiolabeled leukocytes requires an inflammatory process involving neutrophils predominantly (56). However, most cases of FUO may have lesions with predominant monocytic or lymphocytic infiltrations, which are unlikely to give a positive scan with In-111/Tc-99m labeled leukocytes (56). However occult infection may also be associated with neutrophilic infiltration. (56). Reports suggest that pure neutrophils and mixed leukocytes perform equally well in FUO (57). There is also an ongoing debate as to which radionuclide to use. In general Tc-99m has many useful characteristics of an ideal agent but could be less useful in FUO, the reason being that, undiagnosed fevers are usually low grade and chronic in nature, which would call for a delayed imaging at 24-48 hours. Tc-99m has a shorter half-life with decreased stability in labeled cells and non-specific bowel activity limits its use at 24 hours (58). Tc-99m HIG is also used to investigate undiagnosed fever since it is a marker of increased endothelial permeability and accumulates at sites of pathology as a result of non- specific leakage into the interstitial space (56). However, more studies with comparison with other agents are warranted. Antibodies such as Tc-99m Leukoscan have a less defined role at present (Figure 5). There has been some indication that PET may be of use in this patient group, but at present there is very little consistent evidence to show that PET, at least using F-18 FDG, will be of great value in such patients, though there are a few anecdotal evidence of efficacy (54). These patients may have an increased exposure to invasion by many organisms, which would normally, only colonise those patients who have normal immunity. It may be possible for them to have more than one infection and as the host's immune response is reduced to present with attenuated clinical symptoms. The causes of the patient's immunosupression may be congenital, due to drugs, either chemotherapy or anti-transplant rejection drugs or due to infection such as HIV. It is not unusual for patients to suffer unusual infections not seen in normal patients, for example pulmonary infection with Pnemocystitis carinii (PCP) remains a major cause of death and morbidity in patients withAIDS (59). Gallium-67 citrate scanning of the chest was recognized as a more sensitive means of detecting PCP than plain chest radiographs before the advent ofAIDS (Figure 6) (Table 4). Kramer et al reported high sensitivity of 98 % for Gallium- 67 scanning for detection of PCP. Reports suggest that specificity for PCP is increased in patients with scans showing diffuse uptake of Gallium-67 particularly when the pattern is heterogeneous (60-63). Localization of Gallium-67 uptake is also useful in directing the Immunodeficiency syndrome / Human immunodeficiency virus (HIV) infection 134 Gnanasegaran G, Croasdale J, Buscombe JR
  9. 9. References 1. Wegener WA, Alavi A. Diagnostic imaging of musculoskeletal infection. Roentgenography; gallium, indium-labeled white blood cell, gammaglobulin, bone scintigraphy; and MRI. Orthop Clin North Am. 1991; 22(3):401-18.Review 2. Shirtliff ME, Mader JT. Acute septic arthritis. Clin Microbiol Rev 2002; 15(4):527-44 3. Shirtliff ME, Mader JT. Current Treatment Options in Infectious Diseases 2003; 5:323335, Current Science Inc.ISSN 1523-3820 4. Butt WP. The radiology of infection. Clin Orthop 1973, 96:2030. 5. Cardinal E, Bureau NJ, Aubin B, Chhem RK. Role of ultrasound in musculoskeletal infections. Radiol Clin NorthAm 2001, 39:191201. 6. Tehranzadeh J, Wong E, Wang F, Sadighpour M. Imaging of osteomyelitis in the mature skeleton. Radiol Clin NorthAm 2001, 39:223250. 7. Modic MT, Feiglin DH, Piraino DW et al. Vertebral osteomyelitis: assessment using MR. Radiology 1985, 157:157166. 8. Erdman WA, Tamburro F, Jayson HT et al. Osteomyelitis: characteristics and pitfalls of diagnosis with MR imaging. Radiology 1991, 180:533539. 9. Maurer AH, Chen DC, Camargo EE et al. Utility of three-phase skeletal scintigraphy in suspected osteomyelitis: concise communication. J Nucl Med 1981; 22:941949. 10. Alazraki N. Musculoskeletal imaging. In: TaylorA, ed. Clinical Practice of Nuclear Medicine. New York. Chirchill-Livingstone, 1991, pp 379-431. 11. Palestro CJ. Musculoskeletal infection. Nuclear MedicineAnnual 1994; Ed. Freeman LM. Raven Press Ltd, NewYork, 91-119 12. Lipsky BA. Osteomyelitis of the foot in diabetic patients. Clin Infect Dis. 1997; 25: 1318-26. 13. Al-Sheikh W, Sfakianakis GN, Mnaymneh W et al. Subacute and chronic bone infections: diagnosis using In-111, Ga-67 andTc-99m MDPbone scintigraphy, and radiography. Radiology 1985; 155: 501-506 14. Von Rothenburg T, Schaffstein J, Ludwig J, Vehling D, Koster O, Schmid G. Imaging osteomyelitis with Tc- 99m-labeled antigranulocyte antibody Fab' fragments. bronchoscopy for transbronchial biopsy leading to a diagnosis of PCP. In cases with very intense heterogeneous uptake of Ga-67 throughout the lungs and a negative chest X-ray, one should have a high suspicion for PCP. Lung Tc-99m DTPAtransfer/permeability has been widely used to assess the integrity of the lung alveolar-capillary interface (52,64). Pneumocystis carinii pneumonia (PCP) is the most common cause of pneumonia in HIV antibody positive patients. The presence of a biphasic, rapid transfer curve indicates severe extensive alveolar damage and is seen in PCP or legionella pneumonia (65). Tc-99m DTPA transfer/permeability measurement is a rapid, easy method of evaluating patients with HIVdisease (52,64). Polyclonal human immunoglobulin (HIG) is a non-specific agent. Tc-99m HIG has been used to image patients with AIDS and it was found to be inferior to Gallium in imaging chest and abdomen (66). This was thought to be due to increased blood pool, which was found to be significant even at 24 hours post injection (66). In direct comparison with Ga-67 in 25 patients with AIDS presenting with fever the sensitivity of Tc-99m HIG was only 55% and 8 positive sites detected by Ga-67 was found to be negative with Tc- 99m HIG (66). In-111 labeled leukocytes may be used for the detection of pulmonary infections or inflammatory conditions inAIDS. Ga-67 citrate, however, is more sensitive (100%) for diffuse processes showing greater uptake than In-111 labeled leukocytes (sensitivity 40%) in patients with PCP (67). Goldenberg et al reported a sensitivity of 85 % and specificity of 86.7% for PCP using a Tc-99m labeled Fab fragment of a murine monoclonal antibody to PCP (68). In general, radionuclide techniques are sensitive for the detection of PCP, especially Ga-67 scans; however, they lack in specificity for PCP. Patients with HIV could suffer from a dementia type illness related to low-grade encephalopathy (HIV encephalopathy). Cerebral perfusion studies with Tc-99m HMPAO (SPECT) and F-18 FDG are reported to be useful (69). With both these agents a marked reduction of cerebral perfusion is seen in the medial temporal lobes, followed by reduction in the frontal and posterior lobes. Also a patient with T lymphocyte immunosuppression either from HIV or the administration of anti-T- lymphocyte globulin (ATG) can suffer from a primary cerebral lymphoma or toxoplasmosis. Though lymphoma is uni-focal and toxoplasmosis is multi-focal, often there is an overlap. Tl- 201 is reported to be useful in differentiating them both as uptake in cerebral lymphoma is found be 7 times greater than the normal brain or brain infected with toxoplasmosis (70). In bone and joint diseases radionuclide imaging remains as an effective and accurate method of diagnosis. The use of three-phase bone scans followed by a specific infection imaging study enables most patients to be correctly diagnosed. In the suspected prosthetic joint the use of radiolabeled leukocytes, Infecton and leukoscan, possibly Conclusion World Journal of Nuclear Medicine, Volume 4, Number 2, April 2005 135 with additional bone marrow imaging provides the best method for localizing disease. In patients with fever of unknown origin Gallium-67 is still the first choice, though PET may have more use in the future. In most of these patients nuclear medicine provides both unique and clinicallyusefulinformation. Acknowledgements Dr. Gopinath Gnanasegaran was funded by the Special Trustees of the Royal Free Hospital, London, United Kingdom. Gnanasegaran G, Croasdale J, Buscombe JR
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