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Rationale and Objectives The role of transthoracic needle biopsy (TTNB) in patients with hematologic malignancies, particularly in discriminating between malignant and benign etiologies, has not been well studied. Hence, the diagnostic efficacy and safety of computed tomography–guided TTNB were retrospectively evaluated in this population. Materials and Methods The records of 53 patients with hematologic malignancies who underwent TTNB from August 1, 1999, to July 31, 2007, were reviewed. Potential factors for increased diagnostic yield and risk for complications were collected and analyzed, including the status of neutropenia, thrombocytopenia, chemotherapy, and transplant as well as lesion size and location. Both cytopathologic and microbiologic results were assessed. Results The most common underlying hematologic malignancy was non-Hodgkin lymphoma, in 20 patients (37.7%). Lesions were most frequently located in the left upper lobe (16 [30.2%]); 33 lesions were pleural based (63.5%), and nine had cavitation (17.0%). TTNB established specific diagnoses in 22 patients (41.5%): malignancies was found in 12 (22.6%) and infections in 10 (18.9%). Sensitivity for detecting malignancy was 50.0%, and sensitivity for the detection of a specific infection was 40.0%. There were no false-positive results. Complications occurred in nine patients (17.0%): self-limited small-volume hemoptysis in one patient (1.9%) and pneumothorax in eight patients (15.1%), one requiring chest tube placement. The results of TTNB led to changes in antimicrobial therapy for eight of the 22 patients with specific diagnoses (36.4%). Conclusions TTNB is a safe diagnostic procedure in patients with hematologic malignancies and has the potential of making specific diagnoses with minimal morbidity.

Stavudine, a potent antiviral agent for treating human immunodeficiency virus (HIV) infections, was radiolabeled with (11)C by methylation of a specifically designed precursor, 5'-O-(2-tetrahydropyranyl)-5-bromo-2',3'-didehydro-3'-deoxythymidine, with (11)C H(3)I. The radiolabeled drug was isolated by reverse phase HPLC. A total time of approximately 45 minutes was required for synthesis, purification and isolation of (11)C stavudine with chemical and radiochemical purities of greater than 98%. (11)C stavudine was combined with unlabeled drug (2.0 mg/kg) and used to study its pharmacokinetics in rats by measurement of radioactivity in excised tissues. In this species, there was rapid accumulation of drug in all tissue. In all tissues, with the exceptions of testis and brain, highest concentrations of drug were detected at 5 minutes after injection and decreased monotonically thereafter. The peak concentration (microg/g) of stavudine in blood was 1.78 +/- 0.16 and similar levels were achieved in most other tissues; heart 1.66 +/- 0.11, lung 1.60 +/- 0.15, liver 2.13 +/- 0.17, spleen 1.61 +/- 0.15, adrenal 1.47 +/- 0.20, stomach 1.40 +/- 0.11, GI tract 1.44 +/- 0.14, skeletal muscle 1.38 +/- 0.15 and bone 1.30 +/- 0.16. Much higher peak concentrations were achieved in kidney; 7.23 +/- 0.57 microg/g. Concentrations in testis were lower and remained relatively constant over 1 hour; peak 0.62 +/- 0.14 microg/g at 15 min Brain concentrations were low but increased monotonically over time; peak 0.26 +/- 0.02 microg/g at 60 min. Future PET studies with this radiopharmaceutical will allow in vivo measurements of the pharmacokinetics of stavudine in both animal models and human subjects.

Background & Aims: Adefovir dipivoxil possesses potent in vitro and in vivo antiviral activity in wild-type hepatitis B. This study assessed the safety and efficacy of adefovir dipivoxil alone and in combination with lamivudine compared with ongoing lamivudine therapy in patients with chronic hepatitis B with compensated liver disease and lamivudine-resistant hepatitis B virus (HBV). Methods: Fifty-nine hepatitis B e antigen (HBeAg)-positive patients with genotypic evidence of lamivudine-resistant HBV, serum alanine aminotransferase (ALT) level ≥1.2 times the upper limit of normal, and serum HBV DNA level ≥6 log 10 copies/mL despite ongoing treatment with lamivudine were randomized to adefovir dipivoxil 10 mg, lamivudine 100 mg, or addition of adefovir dipivoxil to ongoing lamivudine daily. The primary end point was the time-weighted average change from baseline in serum HBV DNA level (DAVG) up to week 16. Results: Rapid reductions in serum HBV DNA level were seen by 4 weeks in all recipients of adefovir dipivoxil; DAVG 16 was −0.07 in the lamivudine group compared with −2.45 and −2.46 log 10 copies/mL in the adefovir dipivoxil/lamivudine and adefovir dipivoxil monotherapy groups, respectively ( P 10 copies/mL in the lamivudine, adefovir dipivoxil/lamivudine, and adefovir dipivoxil groups, respectively. ALT level normalized in 10 of 19 (53%) and 9 of 18 (47%) recipients of adefovir dipivoxil/lamivudine and adefovir dipivoxil, respectively, compared with 1 of 19 (5%) recipients of lamivudine. Three patients receiving adefovir dipivoxil or adefovir dipivoxil/lamivudine and none receiving lamivudine monotherapy were HBeAg negative at week 48 and one became hepatitis B surface antigen negative. Conclusions: These data, limited to patients with compensated liver disease, indicate that adefovir dipivoxil alone or in combination with ongoing lamivudine therapy provides effective antiviral therapy in patients with lamivudine-resistant HBV.

Cytomegalovirus (CMV) remains the most important infection affecting heart-transplant recipients. Treatment of clinical disease is with a two to three-week course of intravenous ganciclovir, which is effective in more than 90% of individuals. However, relapsing disease, particularly in those with primary infection, is an increasing problem, occasionally with the development of ganciclovir-resistant infection. In those instances, foscarnet is needed, despite its nephro- and neurotoxicities. Increasingly, in order to prevent relapse, more prolonged oral courses of anti-viral therapy are being added to the standard two to three-week course of intravenous treatment. In the prevention of CMV disease, those at risk of primary disease (donor seropositive, recipient seronegative) should receive prophylaxis; for seropositive transplant patients, preemptive strategies linked to immunosuppression or viremia monitoring are becoming increasingly prevalent. In the future, as new drugs become available, the essential question will be whether chronic allograft injury (i.e., accelerated coronary artery atherosclerosis) can be prevented with an anti-viral strategy.

The occurrence of urinary tract infection and its clinical impact is determined, as with any infectious disease, by the interaction between the virulence of the infecting organism and the host defense mechanisms that can be mobilized. In the case of urinary tract infections, an anatomically and functionally intact kidney and urinary tract are the primary host defenses, with phagocytic function and immune mechanisms coming into play to limit the consequences of those infections. Of all the categories of immunocompromised hosts, the renal transplant patient is the one most susceptible to the direct and indirect consequences of urinary tract infections. In the first 3 months post transplant, the incidence of urinary tract infection is greater than 30%, and there is a relatively high rate of bacteremia and overt pyelonephritis of the allograft. After this time period, unless anatomic or functional derangement of the urinary tract is present, the direct clinical manifestations are far more benign. In addition to the direct effects of urinary tract infection on these patients, indirect effects are also important. These include the activation of CMV by TNF released as a consequence of a urinary tract infection and the initiation of allograft injury. Fortunately, low-dose trimethoprim-sulfamethoxazole or fluoroquinolones are safe and effective prophylactic strategies for preventing the direct and indirect consequences of urinary tract infections. Although the pathogenetic mechanisms are incompletely understood, data are emerging that AIDS patients have both an increased incidence and severity of urinary tract infection. The risk for urinary tract infections seem to be correlated with the degree of immune compromise and, perhaps, the amount of malnutrition and wasting that are present. The best strategies for preventing urosepsis in AIDS patients remain to be defined.

The effects of cytomegalovirus (CMV) on the liver transplant patient can be divided into two general categories: the direct infectious disease effects (e.g. CMV mononucleosis, hepatitis, pneumonitis, GI infection) and the indirect effects that are mediated by cytokines elaborated as a consequence of the infection. These indirect effects include an immunosuppressive effect that contributes to the development of superinfection with fungi, bacteria, and Pneumocystis carinii; a role in the pathogenesis of allograft injury; and a role in the development of post-transplant lymphoproliferative disease. The two key steps in the pathogenesis of CMV infection-reactivation of the virus from latency and systemic spread-are modulated by the immunosuppressive therapy administered. New antiviral programs, primarily those involving ganciclovir, have resulted in considerable progress in the prevention and treatment of CMV disease among liver transplant recipients.

[18F]CP 99,219 [(1 alpha, 5 alpha, 6 alpha)-7-(6-amino-3-azabicyclo [3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid] was prepared by 18F for 19F exchange followed by reverse-phase HPLC purification. Studies of the effects of reaction time and temperature on 18F incorporation demonstrated that heating 1.0 mg of CP 99,219 in 0.5 cc of DMSO with 4.5 mg of K2CO3 and 24 mg of Kryptofix for 15 min at 160 degrees C results in the optimal compromise between radiochemical yield and purity. This method routinely provides radiochemical yields of 15-30% [EOS] with radiochemical purities of97%. Varying the concentration of CP 99,219 in the reaction mixture had no effect on yield. Biodistribution studies in rats demonstrated that significant concentrations of drug accumulate in most tissues. The tissues with the highest concentrations of drug were intestine, liver, kidney, and stomach.

SUMMARY Considerable progress has been made in elucidating the factors involved in the pathogenesis of infection in the organ transplant patient. One of the general principles that has emerged is that the risk of clinical infection, particularly opportunistic infection, is determined largely by the interaction between the patient's net state of immunosuppression and the epidemiologic exposures the patient encounters. The two major factors that determine the net state of immunosuppression are the nature of the exogenous immunosuppressive therapy that is administered and whether or not infection is present with one or more of the immunomodulating viruses (particularly cytomegalovirus, Epstein-Barr virus, and the hepatitis viruses). Finally, the therapeutic prescription for the transplant patient has two components—an immunosuppressive component to prevent and treat rejection and an antimicrobial component, which is linked to the intensity of the immunosuppressive therapy required, to make this safe. This reflects the recognition that the two major barriers to successful transplantation, rejection and infection, are closely tied together by the current requirement for lifelong immunosuppressive therapy. Progress in one area will have beneficial effects on the other.

Approximately 30% of patients with end stage renal disease who undergo transplantation develop renal failure as a result of their long-standing diabetes mellitus. Therefore, diabetics warrant special attention in considering the infectious disease problems associated with transplantation. The three categories that should be considered in infections affecting the diabetic renal transplant recipient are discussed in this article.

Changes in substance P (SP) receptor concentration have been implicated in neuropsychiatric disorders, Parkinson's disease, arthritis, inflammatory bowel disease and asthma. Since, SP and peptide analogs are rapidly metabolized and do not penetrate into the CNS, they are not useful for PET. Recently, a non-peptide SP antagonist, (+)-(2 S ,3 S )-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994) was developed. As a prelude to PET studies, this compound was radiolabeled with 11 C and biodistribution was determined in hamsters. CP-99,994 was radiolabeled by methylation of tert -Boc, desmethyl CP-99,994 with 11 CH 3 I followed by deprotection and HPLC purification. The time required for the synthesis was 40 min from the end of bombardment. Radiochemical purity of the final product was >95% and specific activity was routinely >1000 mCi/μmol [EOS]. The biodistribution of 11 C-CP-99,994 was determined in groups of six Syrian hamsters at 5 and 30 min after injection. The results of these studies demonstrated that significant concentrations (%ID/g ± SEM) of CP-99,994 accumulate in most tissues of the hamster. The highest levels of drug were detected in the lung: 21.04 ± 1.26 (5 min) and 13.49 ± 1.71 (30 min). Brain accumulation was: 1.44 ± 0.06 (5 min), 1.32 ± 0.05 (30 min). These results indicate that 11 C-CP-99,994 can be prepared in high purity and specific activity. This new radiopharmaceutical may be useful for studying both central and peripheral SP receptors by PET.

The delivery of fleroxacin, a new broad-spectrum fluoroquinolone, to the major organs of the body was studied in 12 normal human volunteers (nine men and three women), utilizing positron emission tomography (PET). Following the infusion of 20 mCi of [ 18 F]fleroxacin in conjuction with a standard therapeutic dose of 400 mg, images were acquired over 8 h. Beginning the next day, the subjects received unlabeled drug at a dose of 400 mg/day for 3 days, with a repeat PET study on the fifth day. Fleroxacin is distributed widely throughout the body, with the notable exception of the central nervous system, with stable levels achieved within 1 h after completion of the infusion. Especially high peak concentrations (⩾18 μ g/g) were achieved in the kidney, liver, lung myocardium, and spleen. The mean plateau concentrations (2–8 h post-infusion, μg/g) were: brain 0.83; myocardium, 4.53; lung, 5.80, liver, 7.31; spleen, 6.00; bowel, 3.53; kidney, 8.85; bone, 2.87; muscle, 4.60; prostate, 4.65; uterus, 3.87; breast, 2.68; and blood, 2.35. Repetitive dosing had no significant effect on the pharmacokinetics of the drug. Since the MIC 90 's of the family Enterobacterioaceae and Neisseria gonorrhoeae are μ g/ml, with the great majority of the individual species ⩾1 μ g/ml, these results suggest that a single daily dose of 400 mg of fleroxacin should be effective in the treatment of infections such as urinary tract infection and gonorrhea.

The serendipitous discovery that radiolabeled nonspecific immunoglobulin G (IgG) accumulates at a site of focal inflammation has led to the development of a new radiopharmaceutical for inflammation scanning, 111 In-IgG. This reagent has been extensively studied in humans with focal infection and has been shown to be both safe and effective. It has been especially useful in the evaluation of patients with possible abdominal and skeletal infection, with the ability to perform serial scans being an important attribute in terms of determining "proof of cure". Preliminary data suggest that this approach may be particularly useful in immunocompromised patients and may find a role in the quantitative assessment of patietns with such nonfectious inflammatory processes as rheumatoid arthritis and inflammatory bowel disease. A new method of labeling IgG with technetium, via the hydrazino nicotinamide derivative, holds promise, in terms of substituting this more practical radionuclide for indium. However, caution must be directed against total substitution, because such processes as suspected vascular or skeletal prosthesis infection may required the longer half-life of 111 In for satisfactory diagnosis. When one compares the results obtained with radiolabeled IgG against the ideal specifications for a radiopharmaceutical to be used for inflammation imaging, most of the requirements are met. The major weakness of this approach is that even with, the technetium-labeled reagent, a minimum of, 6 to 12 hours is necessary for a scant to become positive, which is not acceptable in the evaluation of acutely evolving processes. Development of other radiopharmaceuticals for this purpose remains to be accomplished.

The biological behavior of human polyclonal immunoglobulin G (IgG) radiolabeled with 99mTc via a nicotinyl hydrazine derivative, was evaluated in Rhesus monkeys. 99mTc-IgG and 111In-MACROSCINT DTPA-IgG were co-administered to Rhesus monkeys with focal sites of sterile inflammation and scintillation camera images were acquired at 6 and 19 h after injection. The biodistribution of the two antibody preparations were similar, however, small differences were detected: 99mTc-IgG > 111In-IgG in spleen and lung; 99mTc-IgG in bone and skeletal muscle. A linear correlation of the tissue-to-blood ratios of 99mTc- and 111In-labeled IgG was observed at both times (r2 > 0.98). The slopes of the regression lines were not significantly different from unity: 6 h-0.982 +/- 0.018; 19 h 1.0334 +/- 0.0226. Also, at both 6 and 19 h after injection, the target-to-background ratios (T/B) for the sites of inflammation were remarkably similar for 111In and 99mTc. These studies establish that human polyclonal IgG labeled with 99mTc via a nicotinyl hydrazine modified intermediate is equivalent to 111In-MACROSCINT DTPA-IgG for imaging focal sites of inflammation in monkeys.

We showed previously that large numbers of T lymphocytes accumulate within a few days in the kidneys of rats with ascending pyelonephritis induced with Escherichia coli or Pseudomonas aeruginosa. CD4+ T cells propagated from the lesions exhibited MHC-restricted proliferative responses to formalin-fixed bacteria of the species used to induce infection. In the present study we investigated further the nature of the antigens responsible for the T cell proliferation and studied the ability of different bacterial strains and species to produce proliferative responses. We found that heat-killed bacteria were more stimulatory than formalin-fixed bacteria, and that soluble supernatants of heat-killed organism were also effective. The stimulatory effects of supernatants were destroyed by trypsin and the responses were MHC-restricted. Twelve different E. coli strains, with or without characteristics of uropathogenicity in humans, were all highly stimulatory to T cells derived from a kidney infected with a single E. coli strain. Strains of Klebsiella pneumoniae, Enterobacter aerogenes, and Serratia marcescens--species of Enterobacteriaceae closely related to E. coli--were also stimulatory, whereas more distantly related bacteria--Proteus, Morganella, and P. aeruginosa--were not. T cells propagated from kidneys infected with P. aeruginosa responded to supernatants of this organism, but not to E. coli supernatants. We conclude that a protein antigen (or antigens) shared by strains of E. coli and related Enterobacteriaceae, but not by other gram-negative bacteria, produce MHC-restricted proliferative responses of CD4+ T cells that infiltrate rat kidneys infected with E. coli.

The number of patients who are at an increased risk of life-threatening infection has expanded greatly during the past decade. This expansion is because of two events, one terrible in its consequences, the other very positive. The first is the unprecedented epidemic of opportunistic infection that follows infection with the human immunodeficiency virus or the acquired immunodeficiency syndrome. The second is a direct consequence of the successes of the transplant surgeon, the cancer chemotherapist, the hematologist, and the rheumatologist. The authors review the current issues and trends in understanding and diagnosing infectious complications in the immunocompromised host.

Patient 1. A 24-year-old woman with chronic renal failure secondary to membranoproliferative glomerulonephritis underwent living-related renal transplantation from her 56-year-old mother. Other than her renal disease, she had no significant medical problems. She received cyclosporine, prednisone, and azathioprine as immunosuppressive therapy post transplant. The allograft functioned immediately, and the serum creatinine concentration fell to I . I mg/dl 3 days after transplantation. Because the donor was seropositive for cytomegalovirus (CMV), the patient received CMV hyperimmune globin, 150 mg/kg intravenously every 2 weeks, beginning on the first post-transplant day and continuing until she presented with CMV infection on the 38th post-transplant day. On the 10th day post transplant, the patient's temperature rose to 100.6° F and she felt sick. Physical examination revealed no site of infection, a chest radiograph was normal, and all cultures were negative; the serum creatinine, however, had risen to 1.6 mg/dl. Ultrasound examination of the allograft revealed no fluid collection or evidence of hydronephrosis. A clinical diagnosis of allograft rejection was made, and 500 mg of methylprednisolone was administered intravenously on 2 consecutive days. Although the patient became afebrile, she became increasingly oliguric, and her serum creatinine continued to rise (to 3.2 mg/dl). A percutaneous renal biopsy revealed acute allograft rejection without evidence of cyclosporine toxicity; anti-rejection therapy with OKT3 was initiated at a dose of 5 mg/kg for a total of 14 days. By the end of this course of OKT3, the serum creatinine had returned to normal. The therapeutic program then consisted of cyclosporine, 450 mg/day; prednisone, 20 mg/day; azathioprine, 100 mg/day; one single

A new method of tracing the disposition of fleroxacin was tested in infected and noninfected animals in an effort to develop a technique that might be applicable in humans. [18F]fleroxacin was synthesized and shown to be identical physically, chemically, and in its antimicrobial activity to the commercially produced product. Tracer amounts of [18F]fleroxacin were coinjected with a pharmacologic dose of unlabeled drug (10 mg/kg) into normal mice, rats with focal thigh infection due to Escherichia coli, and normal and infected rabbits. The rats and mice were killed at fixed time intervals after injection, and the concentration of drug was determined by radioactive counting in a well-type counter; the rabbits were studied both by this method and by positron emission tomographic (PET) imaging. These studies validated the reliability of the new approach and suggested that it could be applied safely to humans. In all three animal species studied, delivery of [18F]fleroxacin to most tissues was rapid, with the notable exception of the brain. Accumulation of drug in infected thigh muscle was similar to that in normal muscle. The concentrations of drug reached in various tissues suggest that fleroxacin will be particularly useful in the treatment of gastrointestinal, urinary tract, hepatobiliary, and skeletal infections and that it shows promise for the treatment of lung and soft tissue infection. The minimal concentrations of drug delivered to the brain should decrease the occurrence of central nervous system toxicity with this particular fluoroquinolone.

[4- 18 F]2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propanol ([4- 18 F]fluconazole) was synthesized from its amino precursor. Fieldel-Crafts acylation of 3-fluoroacetanilide with chloroacetyl chloride produced 2′-fluoro-4′-acteamido-2-(1H-1,2,4-triazole-1-yl) acetophenone in 12% yield. Sequential reaction with (1) dimethylsulphoxonium methylide and (2) 1,2,4-triazole followed by in situ hydrolysis resulted in 2-(2-fluoro-4-aminophenyl)-1,3-bis(1H-1,2,4-triazol-l-yl)-2-propanol in 19% yield. A modified Schiemann reaction on this product resulted in [4- 18 F]fluconazole with a radiochemical yield of 1.0–2.0% (EOS) within 2 h. [4- 18 F]Fluconazole was used to measure the pharmacokinetics of fluconazole in rats by measurement of radioactivity in excised tissues and in rabbits by PET. In both species, there was rapid equilibration of [4- 18 F]fluconazole to a relatively uniform distribution of radioactivity in most organs.

The infectious disease clinician and microbiologist have critical roles in assisting the transplant surgeon with decisions regarding safety and appropriate timing of transplantation from an infectious disease standpoint. Following transplantation, the emphasis shifts to rapidly determine the microbiology of specimens obtained from the transplant recipient, and looking for the routine and unusual organisms that may cause classic or unusual presentations of disease. As the number and range of organs being transplanted increase, new infectious disease problems will arise and careful evaluation of specimens, with particular attention to unusual opportunistic pathogens, will continue to allow the infectious disease physician to prescribe effective therapy as promptly as possible.

An ever-increasing population of immunocompromised individuals, including not only the burgeoning AIDS population but also those patients whose host defenses have been damaged by a wide variety of diseases and their therapies, requires prophylaxis against infectious diseases. Existing vaccines can provide some benefit, but the clinician must always be alert to the fact that vaccine response cannot be assumed and such adjunctive measures as antimicrobial prophylaxis (i.e., amantadine during community-wide influenza outbreaks or penicillin prophylaxis against pneumococcal infection in certain asplenics) and/or intravenous immunoglobulin administration should be considered in some patients. In the future, in addition to developing new vaccines, a major effort should be devoted to the development of immunoadjuvants that would increase the effectiveness of vaccine administration.

Peripheral blood T-lymphocyte populations were monitored sequentially in diabetic recipients of renal allografts. Unfractionated buffy coat preparations were reacted with the murine monoclonal antibodies, OKT3 (all circulating T-cells), OKT4 (helper/inducer/regulatory T-cells), and OKT8 (cytotoxic/suppressor cells). Levels of peripheral blood lymphocyte subpopulations of diabetic patients monitored prior to transplantation revealed no significant abnormalities. Following transplantation, but prior to any therapy for acute rejection, the mean percentage of OKT3, 4, and 8 reactive cells in diabetic recipients closely resembled those observed in nondiabetic recipients. After treatment for acute rejection, a marked decrease in the mean OKT4/OKT8 ratio from normal (1.90 ± 0.7) was observed in both diabetic (1.04 ± 0.5), and nondiabetic (1.35 ± 0.5) allograft recipients. Eleven of thirteen diabetic recipients with long-term functioning allografts were found to have a depressed OKT4/OKT8 ratio (mean 1.03 ± 0.6). T-cell subset monitoring of diabetics with end-stage renal failure failed to reveal any significant differences from nondiabetic, uremic patients. The high incidence (75%) of allograft rejection noted in these diabetic allograft recipients similarly suggests normal immunocompetence. Following successful completion of rejection therapy, however, reduction in the ratio of OKT4 to OKT8 reactive cells suggests that an alteration in immune responsiveness has occurred. Immunological monitoring of these long-term diabetic recipients with functioning allografts suggests that the observation of a consistently depressed OKT4/OKT8 ratio may (1) be useful in predicting continued allograft function and (2) prompt the more rapid reduction of steroid medication to maintenance dosage since this pattern may be indicative of subclinical viral infection.

The detection of focal sites of inflammation is an integral part of the clinical evaluation of the febrile patient. When anatomically distinct abscesses are present, lesion detection can be accomplished by standard radiographic techniques, particularly in patients with normal anatomy. At the phlegmon stage, however, and in patients who have undergone surgery, these techniques are considerably less effective. While radionculide methods, such as Gallium-67 ( 87 Ga)-citrate and Indium-111 ( 111 In)-labeled WBCs have been relatively successful for the detection of early inflammation, neither approach is ideal. In the course of studies addressing the use of specific organism-directed antibodies for imaging experimental infections in animals, we observed that non-specific polyclonal immunoglobulin G (IgG) localized as well as specific antibodies. Preliminary experiments suggested that the Fc portion of IgG is necessary for effective inflammation localization. Since polyclonal IgG in gram quantities has been safely used for therapy in patients with immune deficiency states, we decided to test whether milligram quantities of radiolabeled IgG could image focal sites of inflammation in humans. Thus far, we have studied a series of 84 patients with suspected lesions in the abdomen, pelvis, vascular grafts, lungs, or bones/joints. In 48 of 52 patients with focal lesions detected by surgery, computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound (US), the IgG scan correctly localized the site, while 31 patients without focal inflammation had no abnormal focal localization of the radiopharmaceutical. Four patients had false negative scans and one patient had a false positive scan. For this small series, the overall sensitivity and specificity were 92% and 95%, respectively. In this report, we review our experience with this exciting new agent.

Infections of the central nervous system are an important cause of morbidity and mortality in recipients of organ transplants. Three organisms--Listeria monocytogenes, Aspergillus fumigatus, and Cryptococcus neoformans--account for the great majority of such infections. The incidence of these infections is directly related to the patient's net state of immunosuppression and to the epidemiologic exposures he encounters. There is an expected timetable of when particular infections are likely to occur post-transplant. The most important factor in effecting patient survival is the rapidity with which diagnosis is made. Because of the nature of the infecting organisms and the impaired inflammatory response, the clinical presentation of CNS infection is often insidious, making early diagnosis difficult. However, an aggressive approach based upon lumbar puncture and CT scanning for patients with headache and fever or altered states of consciousness can be very rewarding. In addition, the use of such ancillary clues as the results of skin and lung biopsies can be an important clue to disseminated infection, particularly involving the CNS. The recent deployment of the MRI scan in immunosuppressed patients with unexplained CNS symptoms holds particular promise for early diagnosis.

The administration of 0.2 ml of hyperimmune anti-mouse cytomegalovirus (CMV) antiserum intraperitoneally (ip) or intravenously provided complete protection against lethal challenge (10 5.8 PFU ip) with murine CMV. Antiserum protection was complete when the antiserum was administered as long as 24 hr after viral challenge. The administration of antiserum had little effect on the titers of virus in the organs of these animals. Ammonium sulfate-treated antiserum provided similar complete protection. Animals rechallenged with 10 6 –10 6.5 PFU of murine CMV 1 month after initial challenge, at a time when the administrated antiserum was no longer detectable, all survived. We conclude that hyperimmune antiserum can provide significant protection against otherwise lethal murine CMV infection, that the protecting material lies within the immunoglobulin fraction, and that long-term immunity results from the combined exposure to virus and antiserum. Such passive-active protection could be useful in protecting against human CMV infection.

The ability to diagnose and localize vascular graft infections has been a major challenge. Recent studies in animal models and humans with focal bacterial infection have shown that radiolabeled, polyclonal, human immunoglobulin G accumulates at the site of inflammation and can serve as the basis for an imaging technique. This study investigated this new technique for the diagnosis and localization of vascular graft infections. Twenty-five patients with suspected vascular infections involving grafts (22), atherosclerotic aneurysms (2), and subclavian vein thrombophlebitis (1) were studied. Gamma camera images of the suspected area were obtained between 5 and 48 hours after intravenous administration of 1.5 to 2.0 mCi (56 to 74 mBq) of indium 111—labeled, human, polyclonal immunoglobulin G. Scan results were interpreted without clinical information about the patient and were subsequently correlated with surgical findings, other imaging modalities, and/or clinical follow-up. In 10 of 10 patients found to have positive scan results, localized infections were confirmed at the involved sites. In 14 of 15 patients whose scan results were interpreted as negative, no vascular infections were identified at follow-up. The patient with false-negative results and recurrent bacteremia from an aortoduodenal fistula was found to have a negative scan outcome at a time when his disease was quiescent. These data suggest that nonspecific, human, indium 111—labeled immunoglobulin G scanning can be a useful noninvasive means of localizing vascular infections. (J Vasc Surg 1989;10:20–8.)

Natural killer (NK) cell cytotoxicity was monitored in 32 kidney transplant recipients during a double-blind, placebo-controlled trial of interferon alpha prophylaxis. During the first month following transplantation, NK cytotoxicity diminished in both interferon and placebo-treated patients. Thereafter, mean values for NK cytotoxicity decreased further in interferon recipients, whereas they returned toward baseline in placebo recipients. Paradoxically, interferon alpha consistently augmented NK cytotoxicity of all patients in vitro. Various immunosuppressive regimens were employed in these patients. NK cytotoxicity was slightly diminished in patients receiving prednisone and azathioprine, moderately depressed in those who received prednisone, azathioprine, and OKT3 antibody. Three or four placebo recipients with clinically severe cytomegalovirus (CMV) infections had diminished NK cell function. These studies indicate that a variety of factors including exogenous interferon, immunosuppressive regimens, and CMV infections can influence NK cytotoxicity in renal transplant recipients.

Traditional methods of noninvasively evaluating patients for renal injury do not accomplish the following tasks: reliably distinguish potentially treatable forms of acute renal failure from acute tubular necrosis; provide a sensitive indicator of early allograft rejection in renal transplant recipients, particularly those in the pediatric age group; provide an early warning of incipient drug-induced nephrotoxicity; or serve as an adequate screening test for renal injury due to exposure to occupational or environmental toxins, especially heavy metals. Because of this, considerable effort has been devoted to the development of assays to satisfy these needs. Three approaches include measurement in the urine of low-molecular-weight plasma proteins such as beta 2-microglobulin; a variety of kidney-derived enzymes, such as L-alanine aminopeptidase and N-acetyl-beta-D-glucosaminidase; and specific renal antigens using immunologic detection. The first two of these have not proved to be adequately sensitive or specific, complicated by the frequent loss of activity associated with the physicochemical characteristics of the urine or the presence of pyuria. Despite this, useful information has been obtained. In particular, assays of beta 2-microglobulin urinary excretion and retinol binding protein appear to have clinical utility that should be pursued. Recent experience with a monoclonal antibody-based assay for a unique proximal tubular antigen, the adenosine deaminase binding protein, suggests that a battery of such assays, each directed against an antigen localized to a particular segment of the nephron, may be particularly useful.

Twenty-six patients with purulent pericarditis were seen at the Massachusetts General Hospital between 1960 and 1974. The diagnosis was made in 18 of them during life, but only 6 survived, with an over-all mortality rate of 77 per cent. In eight patients, purulent pericarditis developed in the early postoperative period after thoracic surgery. In seven, purulent pericarditis was the result of contiguous spread of infection from a pleural, mediastinal or pulmonary focus in nonsurgical patients. In five patients, it was the result of direct spread to the pericardium from an intracardiac infection. In the remaining six patients, purulent pericarditis developed as the result of a systemic bactermia. Immunosuppressive therapy, extensive thermal burns, lymphoproliferative disease and other systemic processes affecting host resistance were present in at least half the patients. Staphylococcus aureus was the etiologic agent in the largest number of patients (8 of 26 in this report). However, in contrast to previous studies, in a significant number of the patients (five), purulent pericarditis was the result of fungal infection (in three patients subjected to thoracic surgery and in two immunosuppressed patients). This report confirms that purulent pericarditis is an acute disease with a fulminant course. The diagnosis is easily missed since classic signs of pericarditis (including chest pain, friction rub and diagnostic electrocardiographic abnormalities) may be absent. The echocardiogram shows considerable promise in allowing earlier diagnosis of the pericardial effusion which accompanies purulent pericarditis. Optimal therapy consists of prolonged antibiotic therapy and aggressive drainage of the pericardium. In this series, there were 6 survivors among the 11 patients (55 per cent) who received appropriate therapy.

The incidence of infection in the renal transplant patient is directly related to the net immunosuppressive effect achieved and the duration of time over which this therapy is administered. A second major factor in the causation of infections in this population is the nosocomial hazards to which these patients are exposed, ranging from invasive instrumentation to environmental contamination with Aspergillus species, Legionella pneumophila, Pseudomonas aeruginosa and other microbial pathogens. Careful surveillance is necessary to identify and eliminate such nosocomial sources of infection. The major types of infection observed can be categorized according to the time period post-transplant in which they occur: postsurgical bacterial infection in the first month after transplantation; opportunistic infection, with cytomegalovirus playing a major role, and transplant pyelonephritis in the period one to four months post-transplant; and a mixture of conventional and opportunistic infections in the last post-transplant period. Conventional infection in this late period occurs primarily in patients with good renal function who are receiving minimal immunosuppressive therapy; opportunistic infection occurs primarily in patients with poor renal function who are receiving higher levels of immunosuppression.

Forty-nine ambulatory children between 2-1/2 and 12 years of age with acute, clinically uncomplicated urinary tract infections caused by susceptible organisms were randomized to receive a single dose of amoxicillin based on weight or a 10-day course of amoxicillin therapy (conventional therapy). Patients receiving single doses of amoxicillin had a cure rate of 63%, which compares unfavorably with the cure rate of 92% in patients given conventional therapy. A failure of single-dose therapy predicted underlying radiologic abnormalities with a sensitivity of 60% and a specificity of 58%, making it a poor screening test for detecting those patients at risk for renal parenchymal damage. The antibody-coated bacteria assay had no predictive value in separating upper and lower tract disease, although it may predict underlying radiologic abnormalities. The data indicate that the response to single-dose amoxicillin therapy fails to separate upper from lower tract disease reliably and has a limited role in predicting response to conventional antimicrobial therapy.

Six immunocompromised patients housed in widely separated portions of a hospital campus developed invasive aspergillosis during a single month. This represented a significant increase (P less than .001) in the number of cases observed over the 3 years which included this event (19 cases in 36 months). Epidemiological investigation suggested that this cluster of cases was due to a common source outbreak related to construction activity in a central radiology suite serving the hospital. Such non-ward exposures to nosocomial hazards are becoming increasingly important for immunosuppressed hosts.

Salmonellae have demonstrated an extraordinary capacity to adapt to a wide range of ecologic niches and to the peculiarities of modern society, such as the mass production of food products. The vast majority of infections in the United States are caused by serotypes not specifically adapted to human or animal hosts, whereas the most frequent isolate in developing countries is S. typhi, which is highly adapted to human hosts. The number of isolates reported in the United States has been increasing steadily since 1975, largely a result of outbreaks associated with the mass production of food products, particularly poultry, which is frequently contaminated. Salmonella infection occurs when ingested organisms bypass gastric defenses, multiply within the intestinal lumen, penetrate the intestinal mucosa, and multiply within macrophages of the reticuloendothelial system. They may then disseminate via the systemic circulation. Several virulence factors have been identified. The wide range of pathologic and clinical manifestations are subdivided into four syndromes, each requiring a distinct diagnostic and therapeutic approach: (1) gastroenteritis, (2) enteric fever, (3) bacteremia with or without metastatic disease, and (4) asymptomatic carriage. Although any serotype can cause any of these syndromes, certain serotypes are associated with specific presentations. Serious complications of bacteremic infection include infections of the aorta, endocardium, bone, and meninges. Salmonella infection is particularly severe in patients who have AIDS, leukemia, lymphoma, immunodeficiency of other causes, inflammatory bowel disease, schistosomiasis, and macrophage dysfunction. Diagnosis is based on culture of the organism from appropriate sites. Several serologic tests have been developed that warrant further evaluation. Chloramphenicol, ampicillin, amoxicillin, and trimethoprimsulfamethoxazole have clearly established efficacy. Experience with third generation cephalosporins and quinolones is preliminary and fragmentary, but results suggest that they may prove to be efficacious in certain clinical circumstances. Antibiotic resistance has become a major problem in certain geographic areas. The three vaccines for S. typhi that are currently in use internationally provide only moderate protection for short periods of time.

Summary The IgM and IgG make-up of the antirabies antibody response was studied in thirty-nine individuals who received a full course of duck-embryo-derived antirabies vaccine. The IgM response was shown to be greatly prolonged making up 79% and 47% of 'the total antirabies antibody response on the 13th and 27th days after initiation of immunisation, respectively. The prolongation of the IgM response was felt to be due to persistence of antigen caused by the 14 daily shots of vaccine. Since IgM antibody does not leave the circulation and cannot get to tissue sites where it is needed, it is suggested that this response—and, hence, this schedule of immunisation—need modification. Such a modification would be designed to permit the more rapid appearance of high of IgG antirabies antibody.

plex virus (8) have a decrease in the circulating helper-inducer cetl population {OKT4 + lymphocytes), an increase in the suppressor-cytotoxic cell population (OKT8 + lymphocytes), and an inversion in the ratio between the two (normal ~>1.5; in these instances

A patient with hemophilia A and transfusion-associated end-stage chronic liver disease underwent orthotopic liver transplantation. He had no requirement for exogenous factor VIII replacement during the 27 mo he survived. Although his hemophilia was cured, he had antibodies to the human immunodeficiency virus; ultimately he died of complications arising from acquired immunodeficiency syndrome. Liver transplantation for cirrhotic hemophiliacs can free them of the need for antihemophilic-factor therapy; however, application of this approach may be limited by the high prevalence of human immunodeficiency virus infection in multitransfused hemophiliacs.