Acute Rejection Grade Research Articles

Acute rejection following lung transplantation: limitations in accuracy of thin-section CT for diagnosis.

To evaluate the sensitivity, specificity, predictive values, and accuracy of thin-section computed tomography (CT) for the diagnosis of acute rejection following lung transplantation and to determine whether any individual CT abnormalities are associated with histopathologically proved acute rejection. Thin-section CT studies from 64 lung transplant recipients were retrospectively reviewed. CT studies were temporally correlated with various grades of biopsy-proved acute rejection (n = 34); 30 other CT studies were from a control group with no histopathologic evidence of acute rejection. Acute rejection was diagnosed as present or absent, and the diagnostic was calculated. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of CT for the diagnosis of acute rejection were as follows: 35%, 73%, 60%, 50%, 53%, respectively. No individual CT finding was significantly associated with acute rejection. The sensitivity of CT for the detection of various grades of acute rejection was 17% for grade A1, 50% for grade A2, and 20% for grade A3. The combination of volume loss and septal thickening, with or without pleural effusion, was never seen in the absence of acute rejection. Thin-section CT has limited accuracy for the diagnosis of acute rejection following lung transplantation, and no individual CT finding is significantly associated with this diagnosis.

In Vivo Imaging of Acute Cardiac Rejection in Human Patients Using 99mTechnetium Labeled Annexin V

Annexin V binds phosphatidylserine moieties on apoptotic cells. This study reports the initial experience at Stanford University Medical Center with 99mTc-labeled annexin V imaging as a noninvasive measure of apoptosis in acute cardiac rejection. Ten cardiac transplant patients had 99mTc Annexin V imaging and endomyocardial biopsy (EMB) performed within 24 h. No complications related to 99mTc annexin V administration occurred. Eight patients had ISHLT grade of acute rejection of 1A or less. Five patients had two or more areas of uptake noted in the right ventricle on imaging studies. Two of these patients had positive biopsies: one patient had grade 2 rejection with two focal uptake areas and another had grade 3A rejection with three foci. An additional five patients had either one or zero hot spot areas and corresponding negative EMBs. 99mTc-annexin V appears to be well tolerated and may identify patients with acute cardiac rejection.

PANCREAS TRANSPLANTATION: THE HISTOLOGIC MORPHOLOGY OF GRAFT LOSS AND CLINICAL CORRELATIONS

Graft losses due to leaks, bleeding, thrombosis, infections, and early pancreatitis are grouped together under the category of technical failure. Among these complications, massive vascular thrombosis continues to be the most important cause of early graft loss due to technical failure. Pathological evaluation of most allografts lost early in the posttransplantation period shows vascular thrombosis with associated proportional parenchymal necrosis. The morphological findings in allografts that are considered to be lost due to technical failure has not been systematically addressed. In particular, the role of acute rejection in early graft loss has not been well studied. Seventy-four consecutive pancreas graft pancreatectomies were studied histologically to evaluate for thrombosis (recent versus organized), type of vessel involved by thrombosis (arteries, veins, or both), acute rejection grade, chronic rejection grade, endotheliitis, transplant arteritis, coagulation necrosis, acute pancreatitis, presence of infectious organisms, transplant (obliterative) arteriopathy, neoplasia, relative proportions of alpha and beta islet cells, and immunoglobulin and complement deposition. The histological findings were correlated with donor and recipient data as well as clinical presentation. In 23 out of 39 grafts lost in the first 4 weeks posttransplantation, the only pathological changes found were vascular thrombosis and bland ischemic parenchymal necrosis. In these cases, no underlying vascular pathology or any other specific histological change was identified. Most of these grafts (78%) were lost in less than 48 hr and all in the first 2 weeks posttransplantation. Massive vascular thrombosis occurring in an otherwise histologically normal pancreas was the most common cause of graft loss in the first 4 weeks posttransplantation (59%). In most of the remaining cases (33%), although the clinical presentation suggested technical failure, there was clear histological evidence that the massive thrombosis resulted from vascular injury due to immune damage (acute and hyperacute rejection). Increased incidence of early graft thrombosis was seen in grafts from older donors and longer cold ischemia times. After the first month posttransplantation, graft pancreatectomies revealed a wider variety of pathological processes that included severe acute rejection, combined acute and chronic rejection, chronic rejection, and infections. Acute and chronic vascular thrombosis in large and small vessels was commonly seen at all times posttransplantation; chronic, organized thrombosis was strongly associated with chronic rejection. (a) Early acute thrombosis occurring in a histologically normal pancreas defines a true technical failure. This study showed that acute rejection leading to massive thrombosis, which clinically simulates technical failure, results in a significant proportion of early graft losses. (b) Systematic histological evaluation of failed grafts is absolutely necessary for the accurate classification of the cause of graft loss. (c) There is morphological evidence that chronically ongoing thrombosis is an important, common, contributing factor for late graft loss.

Recurrence of giant cell myocarditis in cardiac allograft

Background: Giant cell myocarditis causes essentially irreversible fulminant left ventricular dysfunction with associated conduction abnormalities and congestive failure. Response to immunosuppressive therapy is poor and cardiac transplantation is the only viable treatment option. The histologic hallmarks of giant cell myocarditis include a polymorphous inflammatory response with numerous multinucleated giant cells and extensive myocyte necrosis in a geographic pattern. There were 38 patients who received a cardiac transplant for giant cell myocarditis in the Giant Cell Myocarditis Registry. Among these patients, there were 9 recurrences of disease in the allograft. Concern has been expressed that recurrence of giant cell myocarditis in the allograft might be a contraindication for cardiac transplantation in the future. Methods In our single-center analysis we describe the clinical and histologic findings of 5 patients transplanted for giant cell myocarditis at the Cleveland Clinic. Results All but 1 of the patients were New York Heart Association (NYHA) class 4 with an average cardiac index (CI) of 1.52 liters/min · m 2. Of the 5 patients transplanted, 1 developed recurrent giant cell myocarditis. Routine right ventricular endomyocardial biopsy at 1 week exhibited severe multifocal myocardial fibrosis in addition to mild acute vascular rejection and mild grade 1A cellular rejection. Follow-up biopsy in this patient indicated grade IIIA moderate acute rejection in addition to multinucleated giant cells. Two distinct inflammatory processes were noted consisting of foci of T-cell inflammation identified by immunohistochemistry to be consistent with rejection, and a second inflammatory process with few mononuclear cells staining for macrophage or T-cell markers with eosinophils and myocyte necrosis consistent with giant cell myocarditis. Follow-up right ventricular endomyocardial biopsies (RVBXs) in this patient have subsequently demonstrated improvement in the degree of inflammatory infiltrate without vascular or significant cellular rejection. Vascular rejection was noted in 1 of the remaining 4 patients and was treated successfully with muramab-CD3 and plasmapheresis. Conclusions Giant cell myocarditis should be expected to recur in the allograft and often does so concurrently with rejection. However, the disease in the allograft responds to therapy in a favorable manner, which differs dramatically from that in the native heart. This might be the result of detection of the disease at an earlier stage than in the native heart, or the immunosuppression milieu in the allograft. The favorable response to therapy suggests that the likelihood of recurrence of giant cell myocarditis should not be considered a barrier to transplantation.

Rapidly progressive glomerulonephritis and carcinoma of the hypopharynx

We describe a patient who sought treatment for acute renal allograft dysfunction 2 weeks after renal transplantation. Renal allograft biopsy (RAB) showed intimal arteritis, severe interstitial infiltration with a few eosinophils, and severe tubulitis. Pathologic diagnosis was acute rejection (grade 2b- Banff 93); however, another clinical diagnosis, drug-induced acute interstitial nephritis (AIN), was not excluded. Before the RAB, his trimethaprim-sulfamethoxazole (TMP-SMZ) treatment was discontinued. Renal function began to improve on biopsy day without antirejection therapy. Recovery of renal function without antirejection treatment and discontinuation of TMP-SMZ shows that renal pathology might be related to drug-induced dysfunction and drug-induced AIN and vasculitis. After 5 years, the patient and his renal allograft function are both well.

Correlations between functional changes and different grades of acute rejection in swine small bowel allografts

Correlations between functional changes and different grades of acute rejection in swine small bowel allografts

Incidence, timing, and histologic grade of acute rejection in small bowel transplant recipients

Incidence, timing, and histologic grade of acute rejection in small bowel transplant recipients

An evaluation of the Banff classification of early renal allograft biopsies and correlation with outcome

The Banff classification for assessment of renal allograft biopsies was introduced as a standardized international classification of renal allograft pathology and acute rejection. Subsequent debate and evaluation studies have attempted to develop and refine the classification. A recent alternative classification, known as the National Institutes of Health Collaborative Clinical Trials in Transplantation (NIH-CCTT) classification, proposed three distinct types of acute rejection. The 1997 Fourth Banff meeting appeared to move towards a consensus for describing transplant biopsies, which incorporated both approaches. Patients who received a renal allograft at the Oxford Transplant Centre were managed by a combination of protocol and clinically indicated biopsies. We have undertaken a retrospective analysis of the biopsies correlated with the clinical outcome to test the prognostic value of the original Banff (Banff 93-95) and NIH-CCTT classifications. Three hundred and eighty-two patients received renal allografts between May 1985 and December 1989, and were immunosuppressed using a standard protocol of cyclosporine, azathioprine and steroid. Adequate 5-year follow-up data were available on 351 patients, and of these, 293 had at least one satisfactory biopsy taken between days 2 and 35 after transplantation, the latter patients forming the study group. The D2-35 biopsies taken from these patients, which were not originally reported according to the Banff classification, were re-examined and classified according to the Banff 93-95 protocols. For each patient the biopsy found to be the most severely abnormal was selected, and the Banff and NIH-CCTT grading compared with the clinical outcome. Seven hundred and forty-three biopsies taken from 293 patients between days 2 and 35 after transplantation were examined and the patients categorized on the basis of the 'worst' Banff grading as follows. Normal or non-rejection, 20%; borderline, 34%; acute rejection grade I (AR I), 18%; AR IIA, 6%; AR IIB, 14%; AR III, 1%; AR IIIC, 3%; widespread necrosis 3%. The clinical outcome for the last two groups combined was very poor with 18% of grafts functioning at 3 months and 6% at 5 years. The other groups with vascular rejection (AR IIB and AR III) had an intermediate outcome, graft survival being 78% at 3 months and 61% at 5 years. The remaining four groups (normal, borderline, cellular AR I and AR IIA) had the best outcome: graft survival 95% at 3 months and 78% at 5 years with virtually no difference between the four groups. Three forms of acute rejection, namely tubulo-interstitial, vascular and transmural vascular, were identified, but only the latter two categories were associated with a poor outcome. The eight sub-categories of the Banff classification of renal allograft biopsies are associated with three different prognoses with respect to graft survival in the medium term. These three prognostic groups correspond to the three NIH-CCTT types. The data provide support for the consensus developed at Banff 97 separating tubulo-interstitial, vascular and transmural vascular rejection (types I, II and III acute rejection).

A blinded retrospective analysis of renal allograft pathology using the Banff schema: implications for clinical management.

We sought to determine whether diagnoses established through the Banff schema for evaluation of renal allograft pathology have implications for clinical management, compared with diagnoses established using descriptive terminology. All patients included in this study had mild to severe allograft rejection diagnosed, and, as part of a therapeutic protocol, they received OKT3 as primary anti-rejection therapy. We conducted a retrospective review of their renal allograft biopsy specimens and reclassified them, using the Banff schema, without knowledge of clinical information, laboratory data, or previous biopsy interpretation. Although there is no strict correspondence between descriptive diagnostic terminology and the criteria used in the Banff schema, for the purpose of comparisons, the following approximation was used: mild and mild to moderate rejection=Banff borderline and Banff grade 1, moderate and moderate to severe rejection=Banff grades 2A and 2B, and severe rejection=Banff grade 3. The diagnosis was considered concordant when the diagnosis by descriptive terminology and Banff grading were within the adopted approximation. Of 96 biopsies specimens with mild to severe allograft rejection, 10 were insufficient for diagnosis, and three had changes of chronic allograft rejection. Of the remaining 83 biopsy specimens, 34 (41%) were concordant in interpretation of rejection grades, whereas 49 (59%) were discrepant. The greatest degree of concordance was in grades 2A (66.7%, 18 of 27) and 2B (64.7% 11 of 17), and the lowest was in the borderline category (11.8%, 2 of 17). The greatest degree of discrepancy was in normal and grade 3 (100%, 3 of 3 and 2 of 2, respectively), and the lowest was in grade 2A (33.3%, 9 of 27). Although primary anti-rejection therapy with OKT3 resulted in a high reversal rate of rejection (98%), there were 5 deaths, 12 graft loses, six episodes of serious infections, and three malignancies in this group of patients during a mean follow-up period of approximately 38 months. Because patients with borderline changes and grades 1 and 2A rejection may be treated differently from patients with higher grades (2B and 3), the use of the Banff schema may allow for better adjustment of immunosuppressive therapy in response to specific grades of acute allograft rejection and may result in decreased complications of immunosuppressive therapy.

CONVERSION FROM AZATHIOPRINE TO MYCOPHENOLATE MOFETIL IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS

710 Thirty-six renal transplant recipients, 22 boys and 14 girls, (grafted from 1980 to 1998) were converted from azathioprine (AZA) to Mycophenolate Mofetil (MMF). There were 7 living-related donor grafts and 1 combined kidney-liver transplantation. Mean age at transplantation was 8,8 years (range=1-18.5 yrs). Immunosuppressive tratment was AZA and prednisone (n=4); AZA, prednisone, cyclosporine (n=28); AZA, prednisone, FK506 (n=6). Initial doses of MMF were 600 mg/m2 b.i.d or 300 mg/m2 b.i.d for patients (pts) on FK506. Mean follow-up was 12.6 months (range=1-30). The pts were retrospectively divided into 3 groups according to the time of conversion to MMF related to the age of transplantation. Group 1 (n=8): Conversion to MMF was made during the first year post transplant (mean=4.1 mths). Two pts had cyclosporine nephrotoxicity, 1 had FK506 nephrotoxicity, 4 pts acute rejection (3 with FK506). All were biopsy proven. One pt had psychological intolerance to prednisone. Mean creatinine at the initiation of MMF was 128 μmol/l and decreased to 87 μmol/l after a mean follow-up of 14.3 mths. One pt had acute rejection 18 mths after MMF initiation. Group 2 (n=21): Conversion to MMF was made 1 to 10 yrs post transplant (mean=4.5 yrs). Seventeen pts had chronic transplant nephropathy (CTN) grade I to II, 2 had recurrent nephropathy, 1 had cyclosporine nephrotoxicity, and 1 had an anemia with AZA. Mean creatinine at initiation of MMF was 137 μmol/l. Six pts had a 10% to 25% decrease in creatinine level (follow-up 2.5 to 14 mths), creatinine level was unchanged in 12 pts, and 2 pts resumed dialysis. Anemia was corrected after MMF conversion. Group 3 (n=7): Conversion to MMF was made ≥10 years post transplant (mean=12.6 yrs). All pts had severe CTN. Mean creatinine at initiation of MMF was 255 μmol/l. One pt had a decrease in creatinine level (190 to 160 μmol/l), in 4 pts creatinine level remained unchanged, renal function deteriorated in 1, and 1 resumed dialysis due to non compliance. Of the 36 pts, 21 had 1 or more adverse events: diarrhea (16), nausea and vomiting (4), anemia (6), herpes zoster (2), pneumonia (1), urinary tract infection (1), HBV replication with cytolysis (1). These events led to discontinuation of MMF in 4 pts, interruption in 2, and dose reduction in 17. We conclude that conversion from AZA to MMF in pts with cyclosporine nephrotoxicity, acute rejection, or CTN grade I or II, results in stabilization or improvement in renal function in short term follow-up. However, conversion in pts with severe CTN offers no benefit. High incidence of MMF-related gastrointestinal adverse events necessitates reduced dosages in 50% of pts.

Persistent Increases of BAL Neutrophils as a Predictor of Mortality Following Lung Transplant

To evaluate whether findings from surveillance bronchoscopy predict survival following lung transplantation. Retrospective review and analysis of 498 bronchoscopies with transbronchial biopsy (TBB) and BAL performed in 34 patients after lung transplantation. University-based, tertiary referral medical center. Thirty-four patients after lung transplantation. The mean age at transplantation was 49+/-9 years; 20 (59%) were female. Twenty-four (71%) underwent single and 10 (29%) underwent bilateral lung transplantation. The most common pretransplantation diagnostic groups were emphysema/COPD without concomitant alpha1-antiprotease deficiency (n = 13) and other obstructive disease processes (n = 10). Over follow-up, subjects underwent multiple bronchoscopies with TBB and BAL. The median number per subject was 15 (25 to 75% range 13 to 17). We calculated the overall median BAL WBCs and median percent neutrophils (polymorphonuclear leukocytes [PMNs]) among all of the BALs performed for each subject. We then calculated the mean +/- SD of those median values. We used Cox proportionate hazards to assess mortality risk. The median overall follow-up observation period for the cohort was 560 days. There were 11 deaths during this period. Twenty-four subjects (71%) had acute rejection (AR) grades 2 to 4 (mild to severe), and nine (27%) had obliterative bronchiolitis (OB) diagnosed by TBB at any point. The mean value for BAL WBCs was 366+/-145 x 10(3) per milliliter; for percentage PMNs, the mean was 7+/-10%. Adjusting for age, gender, single vs bilateral lung transplantation, pretransplantation diagnostic group, presence of AR, presence of OB, BAL WBC concentration, and lymphocyte CD4/CD8 ratio, PMN percent was a significant predictor of mortality (p = 0.02). Ongoing inflammation manifested by an increased percentage PMNs over repeated bronchoscopies predicts mortality following lung transplantation. Biopsy data alone may be insufficient to identify posttransplantation patients at risk of poor outcome.

Histologic grading of acute allograft rejection in pancreas needle biopsy: correlation to serum enzymes, glycemia, and response to immunosuppressive treatment.

Allograft rejection continues to be the most common cause of graft failure in technically successful pancreas transplants. Early diagnosis and treatment of rejection is essential for long-term graft survival. Pancreas graft biopsies are now used routinely for the diagnosis of acute allograft rejection. The correlation between clinical evidence of graft dysfunction (increased serum enzymes and glucose), severity of acute rejection on biopsy (rejection grade), and response to treatment has not been previously studied. A total of 151 pancreas transplant needle biopsy specimens from 57 patients were evaluated. Statistical correlation was done between the histologic rejection grade (O-V) and the peak level of enzymes in serum, glycemia, type of antirejection treatment instituted, and response to treatment. Differentiation between grades was also evaluated statistically. Response to antirejection treatment was 25%, 40%, 88%, 78%, 50%, and 17% for grades O-V, respectively. The response for grades II and III was better than for grades 0-I and IV-V (P=0.0003 and 0.0008, respectively). The response to corticosteroids alone was 36%, 86%, 68%, and 0% for grades I, II, III, and IV, respectively. The response to antilymphocyte regimen was 50%, 89%, 85%, 71%, and 17% for grades I, II, III, IV, and V, respectively. Overall correlation between the mean levels of enzymes and rejection grade was seen; the increase of lipase was statistically significant (r=0.24, P=0.012). Amylase and lipase correlated very well with each other (r=0.84, P=0.0001). No correlation was found in the mean values of blood glucose with the serum enzyme increase and with severity of rejection. Hyperglycemia was present in 12 patients; this abnormality in patients with grades II-IV responded promptly to treatment, whereas in patients with grade V, hyperglycemia persisted despite antirejection treatment. Other causes of increased enzymes were found in patients with biopsy specimens showing no rejection (grades 0 and I, 43% and 31%, respectively). Increased serum enzymes, particularly lipase, correlate with the grade of acute rejection, but their lack of specificity precludes their use as sole markers of acute rejection. Glucose levels are not a sensitive marker for acute rejection. Rejection grades II and III are the most responsive to treatment, and a significant proportion of these cases respond to treatment with corticosteroids only. The higher rejection grades (IV and V) require treatment with antilymphocytic regimens, and their overall response to treatment is moderate to poor, respectively.

The use of technetium tc 99m annexin V for in vivo imaging of apoptosis during cardiac allograft rejection

Objective: Apoptosis, or programmed cell death, has been suggested as a mechanism of immunologic injury during cardiac allograft rejection. We tested the hypothesis that technetium Tc 99m annexin V, a novel radiopharmaceutical used to detect apoptosis, can be used to detect cardiac allograft rejection by nuclear imaging. Methods: Untreated ACI rats served as recipients of allogeneic PVG rat (n = 66) or syngeneic ACI rat (n = 30) cardiac grafts. Untreated recipient animals underwent 99mTc-annexin V imaging daily for 7 days. Region of interest analysis was used to quantify the uptake of 99mTc-annexin V. Immediately after imaging grafts were procured for histopathologic analysis and terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate–biotin nick-end labeling of apoptotic nuclei. One group was treated with 10 mg/kg/d cyclosporine (INN: ciclosporin) commencing on day 4 after transplantation (n = 6). Results: Untreated allografts showed histologic signs of rejection 4 days after transplantation. Apoptotic nuclei could be demonstrated in myocytes, endothelial cells, and graft-infiltrating cells of all rejecting allografts. Nuclear imaging revealed a significantly greater uptake of 99mTc-annexin V in rejecting allogeneic grafts than in syngeneic grafts on day 4 ( P = .05), day 5 ( P < .001), day 6 ( P < .001), and day 7 ( P = .013) after transplantation. A correlation between the histologic grade of acute rejection and uptake of 99mTc-annexin V was observed ( r 2 = 0.87). After treatment of rejection with cyclosporine, no apoptotic nuclei could be identified in allografts and uptake of 99mTc-annexin V decreased to baseline. Conclusions: Apoptosis occurs during acute cardiac allograft rejection and disappears after treatment of rejection. 99mTc-annexin V can be used to detect and monitor cardiac allograft rejection. (J Thorac Cardiovasc Surg 1998;116:844-53)

Elevated serum concentrations of cardiac troponin T in acute allograft rejection after human heart transplantation

Objectives. This study evaluates the concept and diagnostic efficacy of using serum troponin T for the detection of cardiac graft rejection.Background. Cardiac troponin T is a cardiospecific myofibrillar protein, which is only detectable in the circulation after cardiac myocyte damage. It might be expected to be released during acute heart allograft rejection, allowing noninvasive rejection diagnosis.Methods. In 35 control subjects and in 422 samples from 95 clinically unremarkable heart allograft recipients more than 3 months postoperatively, troponin T serum concentrations were compared to the histological grade of acute graft rejection in concurrent endomyocardial biopsies.Results. Mean troponin T serum concentrations were identical in control subjects (23.2 ± 1.4 ng/liter) and in heart transplant recipients without graft rejection (International Society for Heart and Lung Transplantation [ISHLT] grade 0; 22.4 ± 1.7 ng/liter). Mean troponin T concentrations increased in parallel with the severity of graft rejection (ISHLT grade 1: 27.8 ± 1.8 ng/liter; grade 2: 33.2 ± 2.7 ng/liter; grade 3A: 54.6 ± 6.5 ng/liter; grade 3B and 4: 105.4 ± 53.7 ng/liter; p < 0.001 for grades 3 and 4 vs. grades 0 and 1). The proportion of positive samples also increased in parallel with rejection severity, reaching 100% in rejections of grade 3B and 4. Sensitivity and specificity for the detection of significant graft rejection (ISHLT grade 3/4) were 80.4% and 61.8%, respectively. The negative predictive value was most remarkable with 96.2%. Intraindividual longitudinal analysis of troponin T levels and biopsy results in 15 patients during long-term follow-up confirmed these findings.Conclusions. The present data demonstrate that acute allograft rejection after human heart transplantation is often associated with increased serum concentrations of troponin T. All cases of serious forms of graft rejection would have been detected before the development of clinical symptoms. Measurement of troponin T levels may become a useful ancillary parameter for noninvasive rejection diagnosis, being most valuable in the exclusion of severe cardiac graft rejection.

MIB-1 as a predictor of response in lung allografts with moderate acute cellular rejection.

The major obstacle that long-term lung transplant recipients face is bronchiolitis obliterans. Prior episodes of acute rejection, specifically their frequency, persistence, and severity, are important predictors of bronchiolitis obliterans. Many cells contribute to the damage of acute rejection, and there is no sole cell type that can predict persistent rejection or bronchiolitis obliterans. In this study we evaluated 48 transbronchial biopsy samples from various grades of acute rejection with the proliferation marker MIB-1 and attempted to retrospectively predict response to standard corticosteroid in a subpopulation of nine responders and nine nonresponders, all with grade A3 rejection. We then characterized the proliferating cells by double labeling with MIB-1 and L26, CD3, OPD4, or KP1. Our results indicate that the proliferating cells in acute lung rejection are a heterogeneous pool of T- and B-lymphocytes, T-helper cells, macrophages, endothelial cells, and possibly parenchymal cells, and that MIB-1 is a valuable tool in the evaluation of total cellular activity in this setting. In addition, the overall proliferation rate, defined as the most intense proliferation rate regardless of location in the biopsy, closely matches the grade of acute rejection. Finally, a low lesional proliferation rate, defined as the proliferation rate at the site of perivascular inflammation diagnostic of acute rejection, is an indicator of excellent response to therapy and may have potential clinical importance.

Exhaled nitric oxide in human lung transplantation. A noninvasive marker of acute rejection.

Acute allograft rejection in animals and humans has been associated with increased nitric oxide production in the graft. Exhaled nitric oxide (ENO) measurement is a noninvasive method of assessing inflammation in airway diseases, e.g., asthma, which might be applicable to lung transplant recipients. Over 12 months, ENO of lower respiratory origin was measured in 108 lung transplant recipients with a mean time after transplant of 1,083 d. ENO (mean +/- SEM; ppb) in stable patients (19.5 +/- 1.1; p < 0.001) was not different from that of healthy controls (23.8 +/- 3.2). ENO was significantly higher in episodes of clinical acute rejection (51.1 +/- 6.3) compared with stable patients but not elevated in bronchiolitis obliterans syndrome (18.6 +/- 1.5) or pulmonary infection (25.9 +/- 4.0). A retrospective analysis of bronchoscopy findings and concurrent ENO (n = 99) showed that ENO did not vary according to histological findings (normal, acute rejection grade I, nonspecific inflammatory change) or with a positive BAL culture. ENO was not correlated with differential lymphocyte and neutrophil counts. ENO appears to be a valid marker of clinical acute rejection in human lung transplantation as distinct from infection or bronchiolitis obliterans. Furthermore, bronchoscopic findings in the absence of a clinical illness were not associated with a rise in ENO.

Sensitivity of Radionuclide Imaging, Doppler, and Gray-Scale Ultrasound to Detect Acute Rejection Episodes, Based on the Pathologic Grade of Acute Rejection

Radionuclide imaging, doppler ultrasound (DUS), and gray-scale ultrasound (US) are well established methods for evaluating both the perfusion and function of newly transplanted kidneys. Acute rejection is generally accepted to be characterized by poor perfusion with decreased uptake and minimal excretion or a deterioration of perfusion and function, as indicated by serial imaging performed at intervals of 2 to 3 days. The aim of this study was to determine the sensitivity of these three imaging modalities to detect acute rejection episodes based on the pathologic grade of Banff classification.

The potential role of mast cells in lung allograft rejection

To perform a retrospective pilot study of the potential role of mast cells in acute and chronic rejection of the lung allograft, transbronchial biopsies of 29 patients with acute rejection and six patients with bronchiolitis obliterans were stained with antibodies to mast cell tryptase. The number of mast cells per unit area were counted, and compared with a control group of normal lung biopsies stained in a similar fashion. Increasing grades of acute rejection were associated with progressively more mast cells per high-power microscopic field. The presence of bronchiolitis obliterans was accompanied by the greatest numbers of mast cells. Mast cells may play a role in the acute rejection response to the lung allograft and in the development of bronchiolitis obliterans.

Selective treatment of early acute rejection after liver transplantation: effects on liver, infection rate, and outcome

Abstract To evaluate the results of selective treatment of biopsy-proven mild acute rejection episodes, we retrospectively studied 1-week liver biopsies of 103 patients with a primary liver graft in relation to liver function tests. The overall incidence of rejection was 35 %. In four patients the biopsy showed histological features consistent with rejection; in 27 patients it showed mild acute rejection (grade 1), and in 5 patients it showed moderate acute rejection (grade 2). Study group 1 consisted of 19 untreated patients with grade 1 rejection and group 2 of 8 treated patients with grade 1 rejection. At 30 and 90 days, no differences in liver function tests were found. The infection rate, histology after 1 year, and survival in the two groups did not differ. It may, therefore, be concluded that withholding treatment in histologically proven mild acute rejection is possible in selected patients based on histological, biochemical, and clinical criteria. This may reflect the functional diversity of morphologically similar lymphocytic infiltrates observed in graft biopsies showing features of mild acute rejection.

Bronchiolitis Obliterans Organizing Pneumonia (BOOP) in Lung Transplant Recipients

We reviewed all tissue specimens from 163 transplant patients (108 double lung transplant [DLT], 55 single lung transplant [SLT]) between November 1983 and January 1994 for abnormalities indicating bronchiolitis obliterans organizing pneumonia (BOOP) and found 17 cases (14 DLT and 3 SLT). Of the three SLTs, BOOP was diagnosed by open lung biopsy (OLB) in two and one was found at autopsy. Of the 14 DLTs, BOOP was diagnosed by transbronchial biopsy (TBB) specimens (9), OLB specimens (2), autopsy (1), TBB and OLB specimens (1), and OLB specimens and autopsy (1). BOOP was found between 1 and 43 months posttransplantation; time of survival from diagnosis was between 2 and 36 months with 9 patients presently alive. Concurrent pathologic diagnosis at the time of BOOP findings were as follows: acute rejection (7) (grade 1 [4] and grade 2 [3]), BO and grade 1 rejection (2), BO and grade 2 rejection (2), BO and Aspergillus infection (1), acute alveolar injury (1), acute alveolar injury and pulmonary embolus (1), acute rejection (grade 1) and Burkholderia cepacia pneumonia (1). No other pathologic diagnosis was found in 1 patient. In total, 11 of 17 patients (65%) had associated acute rejection. Of the 17 patients, 7 subsequently developed BO and 3 had BO before the finding of BOOP. Death occurred in 8 patients (5 DLT and the 3 SLT) between 2 and 6 months after the diagnosis. We conclude that BOOP is an important complication after lung transplantation; it was present in 13% of DLTs and 5% of SLTs. BOOP was most often associated with acute rejection.