Absence of jaagsiekte sheep retrovirus DNA and RNA in bronchioloalveolar and conventional human pulmonary adenocarcinoma by PCR and RT-PCR analysis.

Bronchioloalveolar adenocarcinoma (BAC) morphologically resembles sheep pulmonary adenomatosis (SPA), a contagious ovine pulmonary adenocarcinoma caused by the jaagsiekte sheep retrovirus (JSRV). Previously, positivity for JSRV by immunostaining, reverse-transcription polymerase chain reaction (RT-PCR), and Western blot was reported in most nonmucinous BACs. Our objective in this study was to analyze additional BAC subtypes and conventional adenocarcinomas (CA) to further substantiate this association. Tumor tissue was microdissected from unstained paraffin sections of 26 cases of formalin-fixed, paraffin-embedded BAC (7 mucinous, 17 nonmucinous, 2 sclerosing) and 29 cases of CA. Positive controls consisted of 2 separate paraffin blocks of known SPA. Primer sequences were derived that were capable of hybridizing to all reported strain variants of both the DNA (endogenous) and RNA (exogenous) forms of JSRV. Each sample was tested using both PCR (DNA) and RT-PCR (RNA). All BAC and CA cases were negative for JSRV. Positive controls yielded PCR products that were sequenced and precisely matched the published prototype stain of JSRV. To control for negative effects of tissue fixation, dilutions of positive control tissue were added to BAC and CA samples. Detection of JSRV was evident at 1:50 dilution. Although the possibility of a viral association with BAC cannot be excluded, this study shows that the association with JSRV is probably very weak, if present at all.

Primary pleural effusion posttransplant lymphoproliferative disorder: Distinction from secondary involvement and effusion lymphoma.

Pleural effusion presentation of posttransplant lymphoproliferative disorder (PTLD) is relatively uncommon. Most examples of effusion-based PTLD have been secondary to widespread solid organ involvement, and are associated with an aggressive clinical course. We report on a case of primary effusion PTLD in a 70-yr-old male liver transplant recipient with a history of hepatitis B infection. Cytomorphologically, the pleural fluid specimen showed a monomorphous population of intermediate to large-sized transformed lymphoid cells, with irregular multilobated nuclear contours and readily identifiable mitotic figures. Flow cytometric immunophenotypic studies revealed a CD5-negative, CD10-negative, lambda immunoglobulin light chain-positive, monoclonal B-lymphocyte (CD19-positive/CD20-positive) population. The immunocytochemical stain for CD30 antigen was negative. In situ hybridization study for Epstein-Barr virus (EBV) early RNA (EBER) and Southern blot analysis for EBV terminal repeat sequences were both positive. Southern blot analysis for human herpes virus-8 (HHV-8) was negative. No solid-organ PTLD was identified, and the cytologic results supported the diagnosis of primary effusion PTLD. Immunosuppression was decreased, and 8 mo following the diagnosis of pleural fluid PTLD, the patient was stable and his pleural effusion had markedly diminished. Recognition of primary effusion PTLD and its distinction from PTLD secondarily involving the body fluids and from other lymphomas is important, since the behavior and prognosis appear different.

Dactylaria gallopava infection presenting as a pulmonary nodule in a single-lung transplant recipient.

We describe the first case of a pulmonary nodule caused by Dactylaria gallopava in a lung-transplant recipient. An asymptomatic lung-allograft recipient was found to have a 2-cm nodule in the native lung 450 days after transplantation. Culture of a transthoracic needle biopsy of the solitary pulmonary nodule revealed Dactylaria gallopava. Treatment was initiated with amphotericin B for a period of 21 days followed by oral itraconazole for an 8-month period.

Epithelial cell atypia in bronchoalveolar lavage specimens from lung transplant recipients.

In lung transplant recipients, bronchoalveolar lavage (BAL) is mainly performed to detect infectious agents. However, in addition to microorganisms, epithelial cell atypia may be identified, and determination of its significance is necessary. Specimens obtained at BAL in lung and heart-lung transplant recipients (LTRs) between 1991 and 1998 were examined for the presence of significant cytologic atypia in epithelial cells. Ten cases in 9 patients were identified, and these composed the core of our study. These transplant BAL specimens were compared with 4 BAL specimens with carcinoma from non-transplant patients (NTPs). Fourteen cytologic parameters were evaluated, and clinical and biopsy correlation was made in each case. Significant overlap in cytologic features, including background cellularity, number of atypical cell clusters, number of cells in each cluster, size of cell clusters, contour of clusters, 3-dimensionality, tenacious intercytoplasmic connections, multinucleation, nuclear size, nuclear/cytoplasmic ratio, nuclear membrane irregularity, chromatin pattern, intranuclear inclusions, and nucleolar characteristics, was observed between atypical LTR cases and NTP carcinoma cases. Clinically, all LTR cases derived from nonneoplastic conditions including harvest injury (diffuse alveolar damage), acute cellular rejection, and infections. Our study results show that evaluation of cytologic features alone does not permit differentiation of atypical cells found in nonneoplastic conditions from those in malignant conditions. Clinical and histologic correlation and awareness of the range of atypia seen in posttransplant syndromes is important in correct interpretation of these cases.

Lung transplantation for end-stage pulmonary sarcoidosis.

BACKGROUND: Sarcoidosis is a multi-system granulomatous disease which can cause significant pulmonary morbidity and occasionally be fatal. The long term benefit of lung transplantation for this disorder are unknown. METHODS: A retrospective review was made of nine single lung transplant procedures performed at the University of Pittsburgh between March 1991 and March 1995 in patients with end-stage lung disease secondary to sarcoidosis. Two contemporaneous groups of recipients receiving transplants for COPD (n = 30) and inflammatory lung disease (n = 13) served as control groups. Surviving recipients underwent sequential surveillance bronchoscopy with transbronchial biopsy. RESULTS: All recipients survived beyond post-operative day (POD) 30, with 5 recipients currently alive. One year survival for this group was 6/9 (67%). Eight of the 9 sarcoidosis recipients had sequential lung biopsy procedures. Five of these 8 recipients (62.5%) had recurrence of granulomata in the lung allograft with the mean time to diagnosis of recurrent sarcoidosis being POD 224.2 +/- 291.3 (range POD 21-719). None of these 5 recipients had radiographic evidence or clinical symptoms related to granulomatous inflammation in the allograft. Pre-operative and post-operative spirometric values were available on 8 recipients. Vital capacity significantly improved in all recipients from 1.54 +/- 0.43 litres to 2.55 +/- 0.63 litres by POD 180 and was maintained through the fourth postoperative year (p < 0.05 Wilcoxon Signed Rank). Spirometric values were also compared before and after transplantation in the 5 recipients with granulomata in the allograft. Vital capacity significantly improved in these 5 recipients from 1.53 +/- 0.48 litres to 2.71 +/- 0.71 litres by POD 180 and was maintained throughout the first postoperative year (p < 0.05, Wilcoxon Signed Rank). The prevalence of high grade acute cellular rejection [ACR (histologic grades III and IV)] did not differ from that seen in a contemporaneous group of 30 single lung recipients who received allografts for COPD (p < 0.05 Mann-Whitney U), nor when compared to a group of 13 single lung recipients who received allografts for immunologically mediated lung disease (p < 0.05 Mann-Whitney U). The prevalence of chronic rejection (histologic obliterative bronchiolitis [OB]) in the sarcoidosis recipients was 4/8 (50%). In the controls with COPD recipients the prevalence of OB was 10/30 (33.3%), and in the 13 controls with immunologic disease it was 6/13 (46.2%). There was no significant difference in the prevalence of OB between the sarcoidosis recipients and controls. When analyzed to the fifth year after transplantation, freedom from the development of OB also failed to differ between these 3 groups (p = 0.25, Logrank, Mantel-Cox). CONCLUSIONS: Although granulomatous inflammation in the lung allograft is common following transplantation for sarcoidosis, it is not clinically or radiographically relevant. In addition, the prevalence of high grade ACR and histologic OB is no different when compared to other single lung recipients. For these reasons lung transplantation is a viable alternative for end-stage lung disease secondary to sarcoidosis.

Cytopathology of high-grade papillary thyroid carcinomas: tall-cell variant, diffuse sclerosing variant, and poorly differentiated papillary carcinoma.

Cytologic reports of the aggressive tall-cell and diffuse sclerosing variants of papillary carcinoma have emphasized features such as tall and large cells, increased nuclear size, nuclear pleomorphism, intranuclear pseudoinclusions, three-dimensional tissue fragments, squamous-like cells, and dense inflammatory background as characteristic features. However, the specificity of these features in identifying the particular variants and distinguishing them from other poorly differentiated papillary carcinomas and typical low-grade forms of papillary carcinoma has not been established. The objective of this study was to assess the predictive value of these reported cytologic features. Fourteen cases of high-grade papillary carcinoma consisting of the aggressive variants (tall-cell variant (tcv) and diffuse sclerosing variant (dsv)) and poorly differentiated papillary carcinomas (pdpc) were compared to 18 cases of low-grade papillary carcinoma. Seven cytologic features consisting of the presence of tall and large cells, architectural disorganization, nuclear enlargement, prominent intranuclear pseudoinclusions, nuclear pleomorphism, lymphocytic infiltrate, and squamoid appearance of the neoplastic cells were evaluated. Cytology samples from tcv, dsv, and pdpc consistently demonstrated 3 of the 7 cytologic features (architectural disorganization, nuclear enlargement, and pleomorphism). In contrast, only two of the samples from low-grade cases demonstrated these 3 features. The recognition of these 3 cytologic features had a positive predictive value of 88% and a negative predictive value of 100% for identifying tcv, dsv, and pdpc. The remaining cytologic features were not a consistent feature in the variants, and by cytology alone, distinction between the aggressive variants (dsv and tcv) and pdpc could not be made.

Squamous-cell carcinoma of the pelvis in a giant condyloma acuminatum: use of neoadjuvant chemoradiation and surgical resection: report of a case.

A 60-year-old bisexual male was referred to our institution for management of an unresectable squamous-cell carcinoma of the pelvis arising in a giant condyloma acuminatum. He received neoadjuvant chemoradiation consisting of 5-fluorouracil and mitomycin C with concurrent external beam radiation, followed by posterior pelvic exenteration. The surgical specimen had no residual cancer. In situ hybridization was performed using a human papilloma virus omniprobe for human papilloma virus subtypes 6, 11, 16, 18, 31, 33, and 35. Two years after diagnosis the patient is doing well with no evidence of recurrent disease.

Allograft colonization and infections with pseudomonas in cystic fibrosis lung transplant recipients.

OBJECTIVE: To assess the incidence of pseudomonal infection, colonization, and inflammation in the allograft of lung transplant recipients with cystic fibrosis (CF) as compared with recipients with other end-stage lung disease. DESIGN: Retrospective review. SETTING: University medical center transplant service. PATIENTS: All patients with CF and chronic pseudomonal infection (n=62) and patients with nonseptic end-stage lung disease (n=52) receiving a double lung transplant between October 1983 and March 1996. RESULTS: Fifty lung transplant recipients with CF survived beyond postoperative day (POD) 15 and were subject to sequential bronchoscopy with BAL. Forty-four CF lung transplant recipients had Pseudomonas isolated from the allograft by median POD 15 as compared with 21 non-CF lung transplant recipients (p<0.001) with isolation at median POD 158 (p<0.0001). Thirteen CF lung transplant recipients had histologic evidence of infection when Pseudomonas was isolated as compared with only three of the non-CF lung transplant recipients (p<0.01). These infections occurred earlier in the CF lung transplant recipients (median POD 10 vs 261) (p<0.01). When compared with non-CF lung transplant recipients, CF lung transplant recipients with Pseudomonas isolated but without concomitant histologic infection (colonized) were demonstrated to have increased number of polymorphonuclear cells (PMNs) in the BAL fluid recovered from the allograft (17.66+/-24.94 x 10(6) cells vs 3.46+/-4.73 x 10(6)) (p<0.05). Non-CF lung transplant recipients who became colonized with Pseudomonas also had a greater number of PMNs recovered when compared with non-CF lung transplant recipients who did not have Pseudomonas (22.32+/-34.00 x 10(6) cells vs 0.21+/-0.18 x 10(6)) (p<0.01). Nine of 32 (28%) lung transplant recipients with CF have died from pseudomonal allograft infections, but this is no greater than 4 of 21 (19%) deaths related to Pseudomonas infection in recipients without CF (p=0.34). CONCLUSIONS: Isolation of Pseudomonas from the lung allograft occurs more frequently and earlier after transplantation in recipients with CF. While infections related to Pseudomonas also occur more frequently in recipients with CF, there is no increase in mortality. There is an intense inflammatory response in the lung allograft associated with the isolation of Pseudomonas in recipients with and without CF.

Interleukin 6 and interferon-gamma gene expression in lung transplant recipients with refractory acute cellular rejection: implications for monitoring and inhibition by treatment with aerosolized cyclosporine.

BACKGROUND: The purpose of this study was to correlate cytokine gene expression from bronchoalveolar lavage (BAL) cells and peripheral blood lymphocytes (PBL) with graft histology in recipients with persistent acute rejection treated with aerosolized cyclosporine (ACsA). METHODS: We measured mRNA for interleukin (IL) 6, interferon (IFN)-gamma, and IL-10 in recipients (1) without rejection (n=13), (2) with acute rejection that responded to pulsed methylprednisolone (n=7), and (3) with "refractory" acute rejection that failed to respond to conventional immunosuppression (n=17). In the latter group, ACsA was initiated. RESULTS: BAL cell IL-6 and IFN-gamma were highest in recipients with refractory rejection compared with recipients with steroid-responsive rejection and recipients with no rejection. Improvement in rejection histology occurred in 15 of 17 recipients who were treated with ACsA. IL-6 and IFN-gamma mRNA levels from BAL cells decreased during treatment with ACsA (median IL-6:actin ratio: before treatment, 0.40 vs. after treatment, 0.003, P=0.001; IFN-gamma:actin ratio: before treatment, 0.32 vs. after treatment, 0.04, P=0.001). PBL IL-6 and IFN-gamma mRNA expression also decreased during ACsA treatment after 180 days. Expression of IL-10 mRNA from BAL and PBL did not change during ACsA treatment (0.0 vs. 0.03 and 0.0 vs. 0.02, respectively). CONCLUSIONS: IL-6 and IFN-gamma mRNA expression from BAL cells was highest in those recipients with refractory histologic acute rejection. ACsA was associated with decreased IFN-gamma and IL-6 gene expression in BAL cells and PBL.

Treatment of refractory acute allograft rejection with aerosolized cyclosporine in lung transplant recipients.

Lung transplant recipients who have persistent acute cellular rejection are at increased risk for the development of chronic rejection, the leading cause of reduced long-term survival. This study evaluated the use of aerosolized cyclosporine as rescue therapy for unremitting acute rejection. Between June 1993 and March 1996, 18 patients with rejection that failed to resolve after therapy with pulse steroids and antilymphocyte globulin were enrolled in the study. Aerosolized cyclosporine A (300 mg) treatment was initiated for 10 consecutive days followed by a maintenance regimen of 3 days per week. Efficacy was assessed by graft histologic and pulmonary function testing. With the use of linear regression, results in these patients were compared with those in 23 control patients, matched for histologic acute rejection, who had continued to receive conventional rescue therapy. Two patients were unable to tolerate the treatments and were withdrawn from the study. Significant improvement in histologic rejection occurred in 14 of the remaining 16 patients after a mean of 37 days of aerosolized cyclosporine therapy. Measures of forced vital capacity and forced expiratory volume in 1 second (change in percent predicted/100 days plus or minus the standard error) increased over time in the treated patients whereas the condition of control patients declined despite repeated attempts at conventional rescue (forced vital capacity, aerosolized cyclosporine group, 4.6 +/- 2.9 vs control group -8.1 +/- 1.9, p = 0.001; forced expiratory volume in 1 second, aerosolized cyclosporine group, 2.1 +/- 4.4 vs control group -9.8 +/- 2.6, p = 0.043). Renal and hepatic toxicity during cyclosporine therapy was not observed. The incidence of acute histologic rejection (> or = A2) decreased from 2.49 +/- 0.68 episodes/100 days before aerosolized cyclosporine therapy to 0.72 +/- 0.3 episodes/100 days (p < 0.05). In summary, aerosolized cyclosporine is a safe and effective therapy for acute rejection that has failed to improve with conventional treatment.

Expression of metalloproteinases and tissue inhibitors of metalloproteinases in giant cell tumor of bone: an immunohistochemical study with clinical correlation.

The clinical behavior of giant cell tumors (GCTs) is unpredictable. To gain insight into this tumor's biological behavior, matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) were studied. These substances play essential roles in wound healing and neoplastic invasion and metastasis. Paraffin-embedded tissue was collected from 18 cases of histologically benign GCT, with 17 treated by curettage and 1 by resection. Eight cases showed no recurrence after a minimum of 2.5 years, and 10 had local recurrence. One showed metastasis. Antibodies to MMP-9, MMP-2, TIMP-1, and TIMP-2 were applied by immunohistochemical methods. In all cases, MMP-9 was strongly expressed in giant cells predominantly in a diffuse pattern and was strong but focal in stromal cells. MMP-2 decorated stromal cells and giant cells heterogeneously. TIMP-1 was variably expressed in giant cells of the nonrecurrent cases and was strongly present in a diffuse or patchy distribution in the stromal cells in 6 of 8 cases. However, in 9 of 10 recurrent cases, TIMP-1 was expressed weakly by both giant and stromal cells. TIMP-2 was variably expressed in the giant cells of the nonrecurrent cases, but 6 of 8 nonrecurrent cases showed strong stromal cell positivity for TIMP-2. Weak staining for TIMP-2 was observed in 7 of 10 recurrent cases in the stromal cells and 9 of 10 recurrent cases in the giant cells. These results indicate that expression of MMPs and TIMPs differs in giant cells and stromal cells in the same tumor. More significantly, in contrast to the nonrecurrent giant cell tumors, there is an imbalance in the MMPs and TIMPs in the recurrent tumors with a net excess of MMPs. This unopposed expression of MMPs in GCTs may play a role in breakdown of extracellular matrix and tissue invasion. Finally, these markers may prove useful in predicting behavior in these tumors.

CD44v6 expression in primary bronchioloalveolar carcinoma and conventional pulmonary adenocarcinoma.

CD44 is a family of transmembrane glycoproteins involved in cell-to-cell and cell-to-matrix interactions. Of the CD44 isoforms characterized, the v6 variant has been shown to confer metastatic potential in animal models and its expression has been correlated with aggressive behavior in some human malignancies. In an attempt to provide further insight into the heterogeneous appearance and behavior of bronchioloalveolar carcinomas (BACs), the pattern of CD44v6 staining in five mucinous, five nonmucinous, and eight sclerosing stage I BACs were compared with 12 comparably staged conventional pulmonary adenocarcinomas (CPAs). Formalin-fixed, paraffin-embedded sections were stained with monoclonal antibodies to CD44v6 (clone VFF-7). Neoplastic goblet cells, whether growing in a lepidic pattern in mucinous BACs or in an invasive pattern in CPAs, consistently demonstrated low level expression of CD44v6. In contrast, lepidic growth by neoplastic cells of type 2 pneumocyte or Clara cell differentiation demonstrated high levels in five of five cases of nonmucinous BACs, seven of eight cases of sclerosing BACs, and six of nine cases of CPAs. Similar cells of type 2 pneumocyte or Clara cell differentiation within the scarred area of sclerosing BAC demonstrated an intermediate degree of staining with four of eight cases marking with high levels, whereas none of the nine cases of CPAs with invasion by these cells showed high levels in the desmoplastic areas. From these results, two patterns of CD44v6 expression were recognized in BACs and CPAs. First, the expression appeared to be partly dependent on differentiation as cells demonstrating mucinous differentiation, whether in BACs or CPAs, consistently lacked CD44v6 staining. Second, in cells of type pneumocyte or Clara cell differentiation the expression was dependent on the growth pattern and their relationship to the stroma. High level expression was noted in neoplastic cells growing in a lepidic pattern, whereas those demonstrating invasion gradually lost the expression with increasing degrees of stromal reaction. Thus, the expression of CD44v6 in pulmonary BACs and similarly staged CPAs appears to be different from other human malignancies that have a positive correlation with aggressive behavior.

Aerosolized cyclosporine in lung recipients with refractory chronic rejection.

This study evaluated aerosolized cyclosporine as rescue therapy for lung transplant recipients with unremitting chronic rejection. Nine patients with histologic active obliterative bronchiolitis and progressively worsening airway obstruction refractory to conventional immune suppression received aerosolized cyclosporine. Improvement in rejection histology was seen in seven of nine patients. We compared the changes in the FVC and FEV1 over time using linear regression analysis in these seven histologic responders and nine historical control patients. During the pretreatment period for both the experimental and control groups, the FVC and FEV1 declined at comparable rates. After aerosolized cyclosporine there was stabilization of pulmonary function, whereas in the controls there was continued decline. Cyclosporine blood levels were less than 50 ng/ml 24 h after an aerosolized dose of 300 mg in five patients receiving oral tacrolimus. Nephrotoxicity, hepatotoxicity, and a greater than expected rate of infection was not observed. This study suggests that aerosolized cyclosporine is safe and may be effective therapy for refractory chronic rejection in lung transplant recipients.

Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group.

In 1990, an international grading scheme for the grading of pulmonary allograft rejection was instituted. The use of this classification has resulted in a uniformity of grading which has allowed inter-institutional collaborations and communication unique in allograft monitoring. In 1995 an expanded group of international pathologists convened and revised the original proposal. This article summarizes the updated classification for pulmonary allograft rejection. In brief, acute rejection is based on perivascular and interstitial mononuclear infiltrates. Each grade of acute rejection should mention the presence of coexistent airway inflammation, the intensity of which may also be graded. Chronic rejection is divided into bronchiolitis obliterans--active or inactive--and vascular atherosclerosis--accelerated arterial or venous sclerosis.

Adenovirus pneumonia in lung transplant recipients.

Although Adenovirus (ADV) pneumonia has been documented in bone marrow, kidney, and liver transplantation recipients, it has only been sporadically reported in lung transplantation recipients. Among our 308 lung transplantation recipients, we identified four who developed ADV pneumonia. Formalin-fixed paraffin-embedded biopsy and autopsy specimens on all cases were studied by routine histology, immunohistochemistry (IHC), and by in situ hybridization (ISH) for evidence of ADV, and the results were correlated with the patients' clinical progression. Three of the four patients were children, and all four had a progressive and rapidly fatal course within 45 days posttransplantation. The lungs showed necrotizing bronchocentric pneumonia with tendency to spread diffusely to produce alveolar damage and organizing pneumonia. The occurrence of this rapidly fatal ADV pneumonia mainly affecting the pediatric population, early in the posttransplantation course, suggests that the infection is primary to the recipient with ADV either originating and reactivating in the donor lung or acquired from the upper respiratory tract of the recipient. The characteristic smudgy intranuclear inclusions of ADV, as well as IHC and ISH positivity, were observed in the lungs of all autopsies. Antemortem biopsy demonstration of ADV by inclusion formation, IHC, and ISH was observed in two patients. In another patient, antemortem ADV was shown only by ISH, and the recognition of inclusions was made difficult by coexistent CMV infection. Although IHC and ISH may have the potential for detecting early infection, recognition of the characteristic clinical setting with necrotizing bronchocentric pneumonia and smudgy intranuclear inclusions should alert one to the diagnosis of ADV pneumonia.

Efficacy of inhaled cyclosporine in lung transplant recipients with refractory rejection: correlation of intragraft cytokine gene expression with pulmonary function and histologic characteristics.

BACKGROUND: Refractory rejection is a major cause of morbidity and death among lung transplant recipients. Traditional rescue therapies have proved only modestly successful. We recently demonstrated the safety of inhaled cyclosporine for patients with end-stage chronic rejection; this trial was extended to patients with refractory acute rejection. The present study was to determine whether effective inhaled cyclosporine therapy was correlated with suppression of cytokine gene expression. METHODS: Twelve lung transplant recipients were studied. Maintenance therapy, cyclosporine or FK 506, azathioprine, and prednisone, was continued, and inhaled cyclosporine at a dose of 300 mg/day was added. Pulmonary function testing and histologic characteristics from transbronchial biopsy specimens were used to assess efficacy of therapy. Bronchoalveolar lavage (BAL) and peripheral blood cells were analyzed for the presence of messenger RNA by using 32P-labeled primers of cytokines interleukin-2 (IL-2), IL-6, IL-10, and interferon-gamma (gamma) via reverse transcriptase-polymerase chain reaction. RESULTS: Nine of 12 patients (five with acute rejection, four with chronic rejection) exhibited histologic resolution of rejection within 3 months of inhaled cyclosporine therapy. Pulmonary function (forced expiratory volume in 1 second) improved from pretherapy levels in the patients with acute rejection (p < 0.05). All of the nine histologic responders exhibited 4- to 150-fold decreases (p < 0.05) in IL-6 and interferon-gamma messenger RNA levels in the BAL, whereas the three patients who failed exhibited persistent or increased cytokine profiles. IL-2 and IL-10 in BAL and peripheral blood lymphocyte cytokines were not informative. CONCLUSIONS: These results indicate that inhaled cyclosporine is effective therapy for refractory pulmonary rejection and that its mechanism of action is associated with suppression of proinflammatory cytokines IL-6 and interferon-gamma within the allograft.

Significance of acute bronchitis/bronchiolitis in the lung transplant recipient.

Acute bronchitis/bronchiolitis (ABB) in the lung allograft is characterized by a predominantly neutrophilic infiltrate in the small and large airways and accompanied by other features such as luminal dilatation, mucous plugging, and granulation tissue formation. The etiologies for ABB are varied and depend on the context in which this lesion is found. Fifty-nine biopsies from 49 patients were found to have these changes. By correlating the clinical and histopathologic features we found ABB in one of five clinico-pathologic categories: I) Harvest Injury (9 patients); II) Acute Cellular Rejection (7 patients); III) Bronchiolitis Obliterans Syndrome (14 patients); IV) Infection [prior to the development of bronchiolitis obliterans (OB)] (15 patients); and V) Other Manifestations of ABB (4 patients). In the context of early manifestations of harvest injury (Category I), ABB reflected severe ischemic lung injury with secondary acute inflammation of the airways. The prognosis was poor, with five patients dying and one requiring retransplantation because of irreversible harvest injury within 1 month of transplantation. When ABB was found in the setting of acute cellular rejection (Category II), it represented a severe manifestation of immunologic airway injury with a predominant lymphoplasmacytic response, and was followed by subsequent development of OB in five of seven patients. In those patients with histologically proven OB (Category III), the finding of ABB was present in a scarred or distorted airway and was a manifestation of airway rejection, infection, or both as demonstrated clinicopathologically, Infection-related ABB prior to the development of OB (Category IV) was managed as infection alone in 13 patients, but a coexistent perivascular lymphoplasmacytic infiltrate brought the concern for concurrent infection and rejection process in two patients. Since only two of the 15 patients in this category later developed OB, these patients with infectious ABB alone did not appear to be at a significant risk for the later development of OB. Finally, four patients demonstrated ABB without associated clinical manifestations and were placed in Category V (Other Manifestations of ABB). In this category, ABB was noted to be an indolent finding with all of the patients alive to date and none developing OB. Overall, the interpretation of ABB in the lung transplant setting depends on the recognition of the histologic clues and the clinical context in which one finds this airway lesion.