Imaging inflammation with human polyclonal immunoglobulin: not looked for but discovered.
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Biomedical subjects
Publications and source records attributed to F H Corstens.
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Indium-111-labeled human nonspecific immunoglobulin G (111In-IgG) is a newly developed radiopharmaceutical for imaging infectious and inflammatory foci. This article presents an overview of the literature concerning 111In-IgG scintigraphy. The current theory about the mechanism of accumulation suggests that 111In-IgG accumulates in lesions as a result of enhanced vascular permeability and subsequent entrapment of the radiolabeled protein. Human studies show excellent results in imaging bone and joint, abdominal, and intravascular infection. Of special interest is the ability to depict infectious foci in granulocytopenic patients. The value of 111In-IgG scintigraphy for detection of infection is compared with that of gallium-67, labeled-leukocyte, and technetium-99m (99mTc) nanocolloid scintigraphy. The significance of differences between 111In-IgG scintigraphy and two other new scintigraphic techniques, 99mTc-labeled IgG and 99mTc-labeled murine monoclonal anti-granulocyte antibody BW 250/183, are discussed.
Fab' fragments of the monoclonal antibody OV-TL 3, that recognizes an ovarian carcinoma-associated antigen (OA3), were labelled with 99Tcm using D-glucarate as a ligand. Twenty patients suspected of having primary or recurrent ovarian cancer received intravenously 1 mg of the Fab' labelled with 740 MBq 99Tcm. Both planar and single photon emission computed tomographic (SPECT) scintigraphy were performed up to 30 h after intravenous infusion. In 19 out of 20 patients surgical and histopathological evaluation was performed between 2 and 6 days postinfusion. Imaging results were compared with X-ray computed tomography (CT), ultrasonography (US) and CA 125 serum level. Blood clearance was fast with median t1/2 beta of 9.5 h. Thirty-seven per cent of the injected dose (% ID) was excreted in the urine within the first 24 h, whereas 7% ID was excreted in the 24 h faeces. In one patient with an OA3 negative ovarian carcinoma, radioimmunoscintigraphy (RIS) did not visualize the tumour. In two other patients a benign ovarian cyst was found, also showing no elevated uptake. In 13 out of 17 patients ovarian cancer lesions were detected with RIS, whereas CT and US detected lesions in, respectively, 15 and 12 patients. Of 36 surgically defined tumour deposits larger than 1 cm in diameter, 53% were detected and localized with RIS, whereas CT and US detected 61 and 40%, respectively. Radioimmunoscintigraphy with 99Tcm-OV-TL 3 Fab' is less distressing for the patients but the overall imaging performance is not improved when compared with 111In-OV-TL 3 F(ab')2.
The diagnostic accuracy of scintigraphy performed after injection of indium-111-labeled nonspecific human immunoglobulin G (IgG) was studied in 113 patients with 120 foci of suspected infection in bone (52 chronic and eight acute infections), joints (15 localizations), joint prostheses (37 prostheses), and soft tissue of the locomotor system (eight localizations). All patients also underwent standard three-phase scintigraphy after injection of technetium-99m-labeled methylene diphosphonate. A scan obtained with In-111-labeled IgG was considered positive if focal increasing accumulation was noted over time. In 51 patients (45.1%), the results of scintigraphy were verified with intraoperative cultures, and in 21 patients (18.6%), with needle aspiration. The prevalence of infection was 59%; overall sensitivity, 97%; and specificity, 85%. Use of In-111-labeled IgG enabled correct identification of the presence, site, and extent of infection in 69 of 71 proved foci of infection; 41 of 48 negative studies were correct. Only two infections proved with culture were missed; in both patients, the cultures revealed growth of Staphylococcus aureus in low counts.
PURPOSE: Delineation of focal infection is a major problem in the management of febrile granulocytopenic patients. The utility of indium-111-labeled human nonspecific immunoglobulin G (In-111-IgG), a newly developed radiopharmaceutical for imaging focal inflammation, was reported in patients with adequate WBC counts. In the present study, we investigated whether In-111-IgG scintigraphy could be used to locate infection in granulocytopenic patients. MATERIALS AND METHODS: Granulocytopenic rats with focal infection were imaged after In-111-IgG injection. Thereafter, In-111-IgG scintigraphy was performed in 20 granulocytopenic patients. Images were obtained 4, 24, and 48 hours after injection of 75 mBq In-111-IgG. Scintigraphic findings were compared with clinical, roentgenologic, and ultrasonographic methods and culture results. RESULTS: In the animal model high In-111-IgG accumulation was observed in the infectious focus. In the patients, 13 proven pulmonary, abdominal, joint, and soft tissue infections of both bacterial and fungal origin were detected adequately. In-111-IgG uptake not due to verified inflammation was observed in the large bowel of two patients. A thoracic wall infiltrate showing only mild inflammatory activity was not detected. Small toxoplasmosis lesions in heart, liver, and kidneys were obscured by physiologic In-111-IgG activity in these organs. CONCLUSIONS: In-111-IgG scintigraphy is a useful technique to delineate focal infection in patients with granulocytopenia. Accumulation of the radiopharmaceutical does not appear to be granulocyte-mediated. In-111-IgG is a safe and convenient radiopharmaceutical that probably contributes to the early diagnosis of focal infection in granulocytopenic patients.
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The development of human anti-mouse antibodies (HAMA) may cause problems in radioimmunotargeting studies, but may also improve survival of patients. To identify the presence of HAMA in blood samples from patients intravenously injected with 1 mg of 111In-labeled OV-TL3-F(ab')2, we developed three specific OV-TL 3-based HAMA assays and tested these along with two commercially available nonspecific HAMA assays (Sorin and Immunomedics). The specific assays were positive for HAMA with 10 postinjection serum samples from 7 patients. Eight of the 10 samples were also HAMA positive with one or both nonspecific HAMA assays. Conflicting results were observed with half the number of samples. The two nonspecific assays also reacted positively with another 11 serum samples from 5 patients including their preinjection samples. Despite some contradictory results, the nonspecific HAMA assays identify both pre-existent and Mab-induced HAMA, whereas the specific OV-TL3-based HAMA assays identify specific immune-responses occurring after the OV-TL 3 injection.
This study reports the biodistribution and dosimetry for a monoclonal antibody against ovarian carcinoma. Eight patients received 140 MBq 111In-OV-TL 3 F(ab')2; thereafter gamma camera imaging was performed daily up to 96 hr. By using the conjugated view counting method, activity in the organs was quantitated by phantom calibration and by whole-body measurements using a whole-body counter with the conjugated view counting method. Red bone marrow uptake was derived from regions of interest over the lumbar vertebrae and iliac crest. In both methods, organ uptake varied only slightly with time, having a mean value of approximately 18%, 4%, 6% and 17% of the injected dose in the liver, spleen, kidneys and red bone marrow, respectively. The mean radiation dose to these organs was 0.9, 1.5, 1.2 and 0.5 mGy/MBq. The effective dose equivalent was 0.4 mSv/MBq. In this study, two different methods of uptake calculations, result in similar values of organ uptake.
Osteomyelitis of the foot is a well-known complication of diabetes mellitus. In this study, the validity of 111In-labeled human nonspecific immunoglobulin G (IgG) scintigraphy was studied in 16 diabetic patients with foot ulcers, gangrene or painful Charcot joints. In all patients, plain radiographs, conventional bone scan images and 111In-IgG images were recorded. The results were verified by histologic examination of surgical specimens in patients who did not respond to antibiotic treatment within 2-3 wk (10 lesions) or long-term clinical follow-up of at least 6-mo (16 lesions). On the bone scans, all seven osteomyelitic foci were detected. However, 19 additional foci not due to osteomyelitis were seen. The absence of true-negative bone scans in this study resulted in a specificity of 0%. On the plain radiographs, four of seven osteomyelitis foci were detected; for 111In-IgG scintigraphy, six of seven (sensitivity 57% and 86%, respectively). Plain radiographs correctly ruled out osteomyelitis in 15 of 19 lesions, 111In-IgG scintigraphy in 16 of 19 (specificity 79% and 84%, respectively). All imaging procedures gave false-positive results in penetrating ulcers over the calcaneus in two patients and in one patient with a Charcot joint, most likely due to recent fractures. A false-negative 111In-IgG study was observed in a patient with severe arterial angiopathy. Accurate estimation of probable osteomyelitis was not possible from the results of soft-tissue cultures, since in only 6 of 12 positive cultures, osteomyelitic foci could be proven. Indium-111-IgG scintigraphy can contribute to adequate evaluation of osteomyelitis in diabetic foot complications because it improves specificity when compared to bone scan and radiographic findings and improves sensitivity in comparison to plain radiographs.
The purpose of this study was to evaluate the role of both protein and radionuclide in the accumulation of 111In-labeled human immunoglobulin G (IgG) in infectious foci. In rats with a calf muscle infection, biodistribution was determined 2, 6, 24, and 48 hr after injection of a radiopharmaceutical. For IgG, human serum albumin (HSA) and human immunoglobulin A (IgA), all labeled with 111In, target-to-background (T/B) ratios were similar throughout the study. However, absolute abscess uptake of 111In-IgA was significantly lower. For IgG labeled with 111In, 123I, or 99mTc, similar T/B ratios were found up to 24 hr. After 48 hr, the T/B ratio of 111In-IgG was significantly higher than the T/B ratio of 123I-IgG. The absolute abscess uptake of 111In-IgG was higher than that of 99mTc-IgG at 24 hr and 123I-IgG at 48 hr. In conclusion, the radionuclide appears to be of major importance in the accumulation of radiolabeled proteins in infectious foci. Protein mainly influences blood clearance and distribution in organs. The Fc-gamma receptor is not crucial for accumulation in infectious foci.
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The biological behaviour of 111In-labelled OV-TL 3 F(ab')2 was studied in 22 patients with suspected ovarian cancer. After i.v. injection with 140 MBq 111In-OV-TL 3 F(ab')2 (1 mg) blood samples were taken up to 96 h and urine and faeces were collected throughout the whole study. At surgery, 5 to 7 days post-injection, primary and metastatic tumour tissues, as well as fragments of several normal tissues, were removed and 111In uptake was measured. Blood activity disappeared with half-life values of 6.1 +/- 1.1 and 17.9 +/- 6.5 h. Within 96 h excretion in urine and faeces was 16.1 +/- 2.0% i.d. (mean +/- S.D.) and 3.1 +/- 1.9% i.d., respectively. Mean tissue uptake, expressed as % i.d. kg-1 was 3.9 +/- 1.0 for primary tumour, 11.5 +/- 5.0 for liver and 0.4 +/- 0.1 for several normal background tissues. Higher tumour uptake correlated with a higher detection rate at immunoscintigraphy. However, no strict correlation was found between the amount of tumour uptake and the expression of the monoclonal antibody defined OA3 antigen. Quantitation of organ activity, using region of interest analysis, resulted in mean peak organ activities for the liver of 16% i.d., spleen 9% i.d. and kidney 4% i.d. Distribution data indicate that besides specific antibody-antigen interaction several other mechanisms play a role in uptake in tumour and other tissues.
The aim of this study was to evaluate tests predicting renovascular hypertension. This was done by relating the results of renal vein renin tests, the captopril test, and renal scintigraphic tests to the blood pressure outcome 12 months after relief of renal artery stenosis by percutaneous transluminal renal angioplasty in 31 patients. Cure was seen in eight (26%). Improved blood pressure was obtained in 12 patients (39%), and in 11 patients (35%), the result for blood pressure was a failure. The accuracies of the two mathematical models used to analyze the renal vein renin assays were 44% and 60%. The captopril test showed a sensitivity of 36% and an accuracy of 43%. Renal captopril technetium Tc 99m-labeled pentetic acid scintigraphy gave a sensitivity of 60%. Stepwise logistic regression analysis of clinical variables in relation to blood pressure response revealed age as the only factor significantly related to blood pressure outcome. We conclude that the tests used are unfit for helping select patients for percutaneous transluminal renal angioplasty and that age may have an important influence on outcome.
The vasodilator effect of intravenously administered dipyridamole may be caused by an increase in endogenous plasma adenosine levels. We evaluated the effect of caffeine, an adenosine receptor antagonist, on the diagnostic results of dipyridamole-201Tl myocardial imaging in eight patients with coronary artery disease. Caffeine infusion significantly attenuated the dipyridamole-induced fall in blood pressure and the accompanied increase in heart rate. The infusion of dipyridamole alone resulted in chest pain and ST-segment depressions on the electrocardiogram in four patients, whereas none of these problems occurred when the tests were repeated after caffeine. In six of eight patients, caffeine was responsible for false-negative dipyridamole-201Tl tests. Semiquantitive scores of the dipyridamole-induced 201Tl perfusion defects were decreased by caffeine from 9.0 +/- 0.9 to 2.0 +/- 1.1 points (p less than 0.05). Computerized analysis revealed a caffeine-mediated reduction in the percent reversibility of the images from 46% +/- 16% to 6% +/- 10% (p less than 0.05). We conclude that the use of caffeinated products prior to dipyridamole-201Tl testing may be responsible for false-negative findings.
In 35 patients suspected of an infectious focus, the outcome of scintigraphy with 111In-labeled autologous leukocytes (WBC) and 111In-labeled human nonspecific immunoglobulin G (IgG) was evaluated in a prospective comparative study. Clinical, roentgenologic and microbiologic findings were considered to be proof of the presence of infection or inflammation. In this group of patients with mainly subacute infections, 111In-IgG scintigraphy performed significantly better than 111In-WBC scintigraphy, especially in infections of the locomotor system, but also in various soft-tissue infections. Both techniques showed disappointing results in patients with disseminated yersinia infection and in some patients with tuberculosis. Overall sensitivity and specificity was 74% and 100% for 111In-IgG scintigraphy and 52% and 78% for 111In-WBC scintigraphy, respectively.