Preservation of post-transplant lung function with aerosol cyclosporin.

Post-lung transplant use of aerosol cyclosporin (ACsA) is considered by examining the relationship between deposited aerosol dose and effect. In a sub-study of placebo controlled trials of ACsA as a rejection prophylaxis, 15 drug subjects received aerosol dose quantification tests to gage their ability to effectively deposit the nebulised drug in their transplanted lung(s). A total of seven placebo subjects received mock deposition tests. The deposited doses and mock doses were compared to changes in the forced expiratory volume in one second, at six time points during the 2-yr trial period (ACsA was started within 6 weeks post-transplant). Linear relationships were demonstrated between deposited dose and improvement in lung function in the drug subjects at all intervals. Mock dose data from placebo subjects did not demonstrate similar correlation. Based on these results, subjects were grouped by dose and compared. Subjects depositing > or = 5 mg of the drug in the periphery of their transplant(s) had improving pulmonary function on average. Low-dose and placebo subjects demonstrated declines, more A2-A4 rejection events in the latter portion of the trial, and more chronic rejection beyond the end of the trial. A dose-to-effect relationship is demonstrated for aerosol cyclosporin in terms of pulmonary function and biopsy proven rejection.

Aerosol cyclosporin therapy in lung transplant recipients with bronchiolitis obliterans.

The majority of patients who develop bronchiolitis obliterans, after lung transplantation, die within 2-3 yrs after onset since treatment with conventional immunosuppression is typically ineffective. A case/control study was conducted in lung transplant recipients with biopsy-documented bronchiolitis obliterans to determine whether aerosol cyclosporin use contributed to increased survival. The cases comprised 39 transplant recipients who received open-label aerosol cyclosporin treatment in addition to conventional immunosuppression. The controls were transplant recipients treated with conventional immunosuppression alone. There were 51 controls from the University of Pittsburgh Medical Center and 100 from a large multicentric database (Novartis Lung Transplant Database). Forced expiratory volume in one second expressed as a percentage of the predicted value was an independent predictor of survival in all patients with bronchiolitis obliterans. Cox proportional-hazards analysis revealed a survival advantage for aerosol cyclosporin cases compared to the Pittsburgh control group. A survival advantage was also seen when comparing study cases to multicentric controls. Aerosol cyclosporin, given with conventional immunosuppression to lung transplant recipients with bronchiolitis obliterans, provides a survival advantage over conventional therapy alone.

Neutrophils, unopposed neutrophil elastase, and alpha1-antiprotease defenses following human lung transplantation.

Neutrophils are sequestered in the newly transplanted lung after reperfusion or with infection, rejection, and chronic graft dysfunction. Because unopposed (free) neutrophil elastase (NE) released into bronchoalveolar secretions may injure the lung allograft and impair bacterial clearance, we assessed total neutrophil numbers, myeloperoxidase activity as an index of neutrophil influx and degranulation, alpha1-antiprotease (alpha1-AP) concentrations, and unopposed NE activity in bronchoalveolar secretions from lung transplant recipients. Unopposed NE activity was present in bronchoalveolar lavage fluid (BALF) from recipients transplanted for emphysema associated with alpha1-AP deficiency as well as recipients without such deficiency (171 of 2,137 BALF; 8%). Ten of 17 (59%) recipients with alpha1-AP deficiency who were followed for at least 1 yr after transplant with multiple surveillance and diagnostic bronchoscopies had at least one BALF containing unopposed NE, usually associated with the presence of > or = 10(5) colony forming units/ml BALF of aerobic bacteria. In contrast, 19 of 58 (33%) with emphysema not associated with alpha1-AP deficiency, 8 of 32 (25%) recipients with cystic fibrosis (CF), 6 of 16 (38%) with idiopathic pulmonary fibrosis (IPF), and 11 of 36 (31%) with other indications for transplant had unopposed NE in BALF. alpha1-AP levels were significantly elevated in the early posttransplant time period and could be augmented considerably in alpha1-AP-deficient recipients with episodes of infection or rejection. Our findings indicate that unopposed NE activity can be found in both alpha1-AP-deficient and alpha1-AP-sufficient recipients after transplantation, usually in association with endobronchial bacterial infection.

Rejection after organ transplantation: a historical review.

Progress toward understanding the biochemical basis of human individuality spans centuries, but tissue rejection remains the primary clinical challenge of organ transplantation. This article highlights the chronology of scientific discoveries made in the quest to overcome the rejection associated with transplantation. The purposes of this review are to raise clinicians' awareness of the advances in surgery, genetics, immunology, and immunosuppression that have contributed to the current knowledge of tissue rejection and to indicate potential new directions in this challenging field.

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.

Pulmonary aspergillosis in cystic fibrosis lung transplant recipients.

STUDY OBJECTIVE: To define the prevalence of colonization and infection of the lower respiratory tract (LRT) with Aspergillus in lung transplant recipients with and without cystic fibrosis (CF). DESIGN: Retrospective review. SETTING: Large university lung transplant center. MATERIALS AND METHODS: The postoperative course of 31 CF and 53 non-CF double lung or double lobar transplant recipients receiving allografts from April 1991 to February 1996 was reviewed. All recipients were subjected to surveillance bronchoscopy and biopsy at predetermined intervals and when clinically indicated. BAL fluid (BALF) and biopsy material were examined by appropriate fungal culture and staining techniques. Infection was defined by the finding of tissue-invasive disease on biopsy specimens. RESULTS: Seven of the 31 CF recipients (22%) had Aspergillus isolated from cultures of sputum prior to transplantation. Following transplantation, 15 CF recipients (48%) had Aspergillus isolated from either sputum or BALF, including 4 of the 7 recipients identified with the fungus prior to transplantation. By contrast, 21 of the 53 non-CF recipients (40%) had Aspergillus isolated from the LRT following transplantation, none having had the fungus isolated prior to transplantation. The prevalence of Aspergillus did not differ between these groups (p = 0.51). Infections with Aspergillus occurred in 4 of the CF recipients (27%) and did not differ from the 3 infections (14%) identified in the non-CF recipients (p = 0.36). However, three of the four infections in the CF recipients involved the healing bronchial anastomosis and occurred prior to postoperative day 60. All three of these recipients had Aspergillus preoperatively. Postoperative infection was more common in the CF recipients having Aspergillus preoperatively than in those CF recipients without preoperative Aspergillus (p = 0.02). CONCLUSIONS: Isolation of Aspergillus from the LRT following double lung transplantation is common and generally not associated with tissue-invasive disease. Those CF recipients with Aspergillus isolated in cultures of sputum preoperatively are at risk for postoperative infections with this agent. The healing bronchial anastomosis is particularly vulnerable.

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.

Use of aerosolized colistin sodium in cystic fibrosis patients awaiting lung transplantation.

BACKGROUND: In patients with cystic fibrosis (CF) who are awaiting lung transplant, prolonged exposure to systemic antibiotics has frequently led to airway colonization with resistant isolates of Pseudomonas. This resistance limits the arsenal of effective antimicrobials available for infections after the initiation of immunosuppression and has been considered a theoretical deterrent to lung transplantation. METHODS: Twenty CF transplant candidates with "pan-resistant" Pseudomonas received maintenance antibiotic therapy with aerosolized colistin sodium (75 mg b.i.d.), and intravenous antibiotics were eliminated. Ten other CF candidates did not use colistin sodium. Sputum cultures and antibiotic sensitivities were followed every 3-6 weeks. RESULTS: All 20 candidates (100%) who used aerosolized colistin sodium became colonized with sensitive isolates of Pseudomonas in an average of 45.1+/-20.2 days. In contrast, only 3 of 10 CF transplant candidates (30%) who did not use colistin sodium later became colonized with sensitive isolates. The mean time to spontaneous emergence of sensitive organisms was 144.6+/-48.0 days in candidates who did not use colistin sodium and was significantly longer than in the candidates who used colistin sodium (P=0.007). The occurrence of redeveloping sensitive isolates of Pseudomonas was significantly greater in the candidates who used colistin sodium (P<0.05). Of the candidates who used colistin sodium, six have been transplanted at our institution. In five of these six recipients (83.3%) bacterial cultures taken from the explanted lungs continued to demonstrate sensitive organisms. CONCLUSION: Aerosolized colistin sodium may be a useful therapy to promote emergence of sensitive microbes in CF candidates with pan-resistant isolates of Pseudomonas.

Dose-related reversal of acute lung rejection by aerosolized cyclosporine.

This study evaluated the effectiveness of aerosolized cyclosporine as rescue therapy for refractory acute rejection in lung-transplant patients that is unresponsive to conventional therapy. Over 2 yr, nine allograft recipients with histologic evidence of persistent acute rejection and worsening pulmonary function were enrolled. Twenty-two patients with similar degrees of unremitting rejection served as historical controls. Aerosolization of cyclosporin A (300 mg in 4.8 ml propylene glycol) using an AeroTech II jet nebulizer was instituted daily for 12 consecutive days followed by a maintenance regimen of 3 d/wk. Cyclosporine and tacrolimus blood and plasma levels were maintained within therapeutic ranges throughout this trial. Efficacy was assessed by histologic grade of rejection, interleukin-6 (IL-6) mRNA expression by graft bronchoalveolar lavage cells, and pulmonary function testing before and during cyclosporine therapy. In seven patients, results were correlated to deposition of cyclosporine aerosol in the allograft(s) as measured by radioisotopic techniques. At a mean of 37 d after initiation of aerosolized cyclosporine, graft histology improved in eight of the nine patients. Cellular IL-6 mRNA expression decreased significantly in seven patients (mean IL-6/actin +/- SD, 40.96 +/- 118 versus 0.33 +/- 0.57 [p = 0.038]). Pulmonary function (FEV1), which had decreased posttransplant (over a mean of 347 d of observation) from a best value of 1.98 +/- 0.8 L to 1.59 +/- 0.6 L (p = 0.0077), improved over time (152 d) to a posttransplant value of 1.90 +/- 0.8 (p = 0.025). In the control subjects, FEV1 inexorably declined over a comparable period of observation (best posttransplant value 2.36 +/- 0.86 to 1.32 +/- 0.53, p < 0.0001). There was a strong correlation between cyclosporine deposition in the allograft and improvement in FEV1 (r = 0.900, p < 0.01). Fewer cycles of pulsed corticosteroids (1.4 +/- 0.9 versus 0.2 +/- 0.4, p = 0.011) and anti-thymocyte globulin 0.8 +/- 0.4 versus 0, p = 0.018) and reduced doses of oral prednisone (10.8 +/- 3.1 versus 6.1 +/- 4.2 mg/d, p = 0.026) were observed during treatment with aerosolized cyclosporine. Episodes of pneumonia also were reduced significantly during aerosol therapy (2.6 versus 0.95 episodes/100 d, p = 0.029). Nephrotoxicity and hepatotoxicity did not occur, and no patients withdrew from the study. Aerosolized cyclosporine appears to be safe and effective therapy for refractory acute rejection, but confirmation by a larger, randomized trial is necessary. The correlation observed between deposition of cyclosporine aerosol and physiologic improvement of lung function suggests that there is a dose-response relationship between the concentration of cyclosporine in the allograft and immunologic tolerance.

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.

Lung and heart-lung transplantation at the University of Pittsburgh.

The application of lung transplantation as a treatment modality for patients with severe pulmonary disease has changed dramatically since its inception. At the University of Pittsburgh, the criteria for recipient selection continues to evolve and, in an effort to maximize scarce donor organs, the criteria for donor lung acceptance have been extended. Patient survival during the first 3 years after transplantation continues to improve but longer term survival is limited by infectious complications and chronic rejection. In early studies, the utilization of cyclosporine delivered directly to the lungs via aerosol has resulted in dramatic improvement in pulmonary function in recipients with immune mediated allograft injury and has allowed a reduction in systemic immunosuppression. We are hopeful that interventions such as this will result in prolongation of patient survival with less toxicity.

Lung transplantation for respiratory failure resulting from systemic disease.

BACKGROUND: Lung transplantation for pulmonary failure resulting from systemic disease is controversial. We reviewed our transplant experience in patients with sarcoidosis, scleroderma, lymphangioleiomyomatosis, and graft-versus-host disease. METHODS: This retrospective review examined the outcome of 23 patients who underwent pulmonary transplantation for these systemic diseases. Group 1 included 15 patients with pulmonary hypertension who underwent transplantation (9 for sarcoidosis, 6 for scleroderma), and group 2 included 8 patients with normal pulmonary artery pressures who underwent transplantation (5 for lymphangioleiomyomatosis, 3 for graft-versus-host disease). The incidences of infection and rejection, pulmonary function, and survival were measured and compared with those of patients who underwent transplantation for isolated pulmonary disease. RESULTS: Although there were no differences in the rate of infection between patients who underwent transplantation for systemic versus isolated disease, patients with pulmonary hypertension who underwent transplantation for systemic disease had significantly lower rates of rejection. Four patients with sarcoidosis and 2 with lymphangioleiomyomatosis demonstrated recurrence in the allograft. Survival was similar between patients who underwent transplantation for systemic versus isolated disease. CONCLUSIONS: Patients with respiratory failure resulting from these systemic diseases can undergo transplantation with outcomes comparable to those obtained in patients who undergo transplantation for isolated pulmonary disease.

The importance of bronchoscopy with transbronchial biopsy and bronchoalveolar lavage in the management of lung transplant recipients.

Medical and surgical advances have made lung transplantation a feasible therapy for end-stage lung disease. Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBBx) is an accepted technique for detecting clinically evident rejection and infection in the allograft of symptomatic recipients. The role of TBBx and BAL in managing asymptomatic recipients is less defined. We retrospectively examined the role of bronchoscopy with TBBx and BAL in 1124 bronchoscopy procedures that were performed on 161 lung transplant recipients between January 1, 1988, and December 31, 1993. Bronchoscopy was performed when there was a change in the recipient's clinical condition, to assess the response of the allograft to a prior therapy, and under a surveillance protocol for detecting asymptomatic rejection or infection. Surveillance bronchoscopy was performed according to the following schedule: 10-14 days after transplantation, every 3 mo during the first year, every 4 mo during the second year, and at 6-mo intervals thereafter. Surveillance bronchoscopies were defined as procedures where the physician felt that there was no infection or rejection in the allograft on the basis of a standardized clinical evaluation, which excluded the results of the TBBx and BAL. We compared the clinical impression recorded by the physician on the day of the procedure with the final diagnosis determined after the results of the TBBx and BAL were known. We found unsuspected rejection and/or infection that required therapy in 25% (90/355) of all surveillance bronchoscopy procedures. Most episodes (61/90, 68%) of unsuspected rejection and/or infection occurred in the first 6 mo after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Case report: fluconazole therapy in histoplasma mediastinal granuloma.

A 41-year-old man presented with night sweats, fever, and substernal chest pain approximately 5 months after being treated for community-acquired pneumonia. Chest radiograph revealed a mediastinal mass that was confirmed by computed tomography (CT) of the thorax. During surgery, enlarged paratracheal lymph nodes and a mass surrounding the right lower lobe bronchus and bronchus intermedius were found. Multiple biopsies from the mass showed that it consisted mainly of acellular fibrous tissue, but a small number of fungal forms typical of Histoplasma capsulatum were seen at the edged of the fibrotic reaction. The lymph nodes contained granulomatous inflammation and areas of necrosis, but no organisms were identified. The patient was treated with fluconazole for 6 weeks with resolution of symptoms. After completion of therapy, a follow-up CT scan of the thorax showed involution of the mediastinal mass. There has been no recurrence of symptoms or radiographic abnormalities for 24 months since cessation of fluconazole. This case illustrates isolated mediastinal involvement by histoplasmosis and suggests that therapy with fluconazole at this stage may prevent the often devastating late complications of mediastinal fibrosis.

Recurrence of sarcoidosis in pulmonary allograft recipients.

Lung transplantation is a potentially curative therapy for the end-stage pulmonary sequelae of sarcoidosis. We reviewed the course of five lung allograft recipients with underlying sarcoidosis (S) at the University of Pittsburgh Medical Center and compared them with a control group (C) of 44 contemporaneous transplant recipients with other respiratory diseases. Sarcoid granulomata have developed in the allografts of 4 S, although these lesions have not yet been demonstrated to result in clinically significant abnormalities. In comparison with C, sarcoidosis patients had significantly greater mean grades of acute rejection during the first 3 months after transplantation (2.1 +/- 0.3 versus 1.6 +/- 0.1, S and C, respectively, p < 0.042) and larger proportions of lung biopsies showing more than mild acute rejection (40 versus 18%, p < 0.012) and lymphocytic bronchitis (30 versus 13%, p = 0.02), as well as a greater percentage of polymorphonuclear leukocytes in BAL returns (34.9 +/- 5.4 versus 19.0 +/- 1.6, p < 0.01). The two groups did not differ, however, in frequency of obliterative bronchiolitis, survival, or pulmonary function. We conclude that lung transplant recipients with underlying sarcoidosis are very likely to develop recurrent disease in the allograft and have more severe acute rejection responses, especially in the first weeks after transplantation. Pulmonary transplantation appears to be an efficacious therapy for end-stage sarcoidosis, but the long-term sequelae of the increased acute rejection and recurrent sarcoidosis in the allograft remain to be determined.

Enhanced secretion of immune-modulating cytokines by human lung fibroblasts during in vitro infection with Mycoplasma fermentans.

Fibroblasts may play an important role in the modulation of immune and inflammatory responses through elaboration of cytokines. To test this hypothesis, human lung fibroblasts were isolated from transbronchial biopsy specimens and assayed for production of interleukin-6 (IL-6) and granulocyte/macrophage colony-stimulating factor (GM-CSF). The sources of fibroblasts included lung allografts, recipient lungs obtained at time of transplant, and normal lung tissue removed during tumor resection. During the course of these studies, several early-passage fibroblasts from transplant recipients were observed to contain mycoplasma (MP)-like organisms as detected by extranuclear fluorescent staining with Hoechst 33258. Positive staining cultures were associated with isolation of Mycoplasma fermentans. IL-6 and GM-GSF as measured by ELISA were found to be elevated over 50-fold in conditioned medium from MP-infected fibroblasts as compared with noninfected lines. Treatment of cells with mycoplasma removal agent (MRA) eliminated extranuclear Hoechst fluorescence and significantly reduced the production of these cytokines. Tumor necrosis factor-beta (TNF-beta) induction of IL-6 and GM-CSF was amplified synergistically in infected cultures. No additional production of IL-6 or GM-CSF was observed in infected cultures treated with interferon-gamma (IFN-gamma) despite the ability of IFN-gamma to modestly induce IL-6 in uninfected cultures. Thus, in vitro infection of lung fibroblasts with MP represents a potent stimulus for the production of inflammatory cytokines and, therefore, necessitates rigorous control for these organisms in cell culture studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Benefits of posttransplantation monitoring of interleukin 6 in lung transplantation.

To determine the predictive diagnostic value of interleukin 6 (IL-6) monitoring in lung and heart-lung transplants, we measured posttransplantation serum IL-6 levels in 17 adult lung or heart-lung transplant recipients. Posttransplantation IL-6 elevation patterns were classified into 4 groups: serum IL-6 level remained negative throughout the monitoring period (group 1; n = 1; 6%); several sharp spikes with normal baseline (group 2; n = 9; 53%); persistently high level of serum IL-6 (group 3; n = 3; 18%); and several sharp spikes of serum IL-6 elevation with abnormally high baseline (group 4; n = 4; 24%). One patient without an elevation of IL-6 (group 1) did not experience any episodes of rejection or infection. Nine patients in group 2 had 19 IL-6 spikes, 13 of which were associated with histopathologically or clinically diagnosed rejection, 3 with acute bronchitis, and 1 with diffuse alveolar damage. Three patients in group 3 had persistent infections including cytomegalovirus infection, toxic megacolon, and repeated bacterial infection during the monitoring period, and 4 in group 4 died within 3 months after transplantation. From this study it appears that a spiked elevation of IL-6 could have a predictive value in diagnosing rejection, and persistently high levels of IL-6 indicate the presence of infection. Thus, IL-6 monitoring is beneficial for lung transplant recipients.

Sequelae of cytomegalovirus pulmonary infections in lung allograft recipients.

Indirect effects of cytomegalovirus (CMV) infections in lung transplant recipients (LTX) have not previously been described in detail. We compared spirometric results, development of chronic rejection, rates of respiratory superinfections, and mortality as long as 2 yr after transplantation, between 62 LTX who never developed CMV (CMV-) and 56 LTX with a history of CMV pulmonary infections (CMV+). Initial spirometric parameters were near identical for both groups, but determinations > or = 6 months after transplantation showed that expiratory flows of the CMV+ were significantly reduced. Actuarial prevalences of chronic allograft rejection (CR) at 2 yr were highest among CMV+ with biopsy-proved pneumonitis (74%) compared with 22% among CMV- (p < 0.038). Bacterial or fungal pneumonias developed in 58.9% of the CMV+, whereas the rate among CMV- was 38.7% (p < 0.05). Only 36% of LTX with CMV pneumonitis lived 2 yr compared with 70% survival for CMV- (p < 0.016). Ganciclovir treatment of CMV infections decreased rates of respiratory superinfections and improved survival of patients, but it did not appear to affect subsequent development of CR. We conclude that CMV pulmonary infections among LTX result in serious late sequelae and that current treatment is ineffectual for prevention of viral-associated CR in these patients.

Acute rejection of lung allografts with various immunosuppressive protocols.

Between February 1990 and December 1991, 69 patients who survived for a minimum of 5 days after single-lung (27), double-lung (32), or heart-lung transplantation (10) were studied to learn the incidence and severity of acute rejection and the possible effects of various immunosuppressive protocols on this rejection. Acute rejection was less common (2.1 versus 3.1 episodes/patient) after transplantation in those 30 candidates who received rabbit antithymocyte globulin for the first 5 postoperative days versus the 28 who were maintained on cyclosporine, azathioprine, and prednisone alone (p < 0.05), but no patient escaped at least one episode. Patients given cyclosporine received more 3-day courses of methylprednisolone (p < 0.02) than those given rabbit antithymocyte globulin (2.5 versus 1.7 courses). Although no disadvantage in terms of infectious morbidity was noted in the rabbit antithymocyte globulin group, no obvious intermediate advantage was noted in survival (85% at 12 months) or grade of rejection or airway flows. The most common histopathologic grades were mild (A2) and moderate (A3); the average grade was A2.3. FK 506 was tested in 11 patients, and early results are promising relative to low early and likely fewer late episodes of rejection. No differences were noted in the likelihood of rejection for any procedures.

Ganciclovir prophylaxis for cytomegalovirus infections in pulmonary allograft recipients.

Cytomegalovirus (CMV) is a substantial cause of morbidity in pulmonary allograft recipients. In an attempt to decrease the prevalence of this infection, we treated 13 recipients at risk for cytomegalovirus with 3 wk of intravenous ganciclovir (5 mg/kg twice a day for 14 days, starting 5 days after the procedure, followed by 1 wk of the drug at a dose of 5 mg/kg/day). Following the ganciclovir course, patients received oral acyclovir, 800 mg three times a day for at least 2 months more. CMV infections developed in 5 recipients (38%), and none of these episodes occurred during the ganciclovir therapy. Neither of the 2 deaths in this group could be attributed to CMV. In comparison, the prevalence of CMV in the preceding cohort of 11 transplant recipients who were administered acyclovir alone was 91% (p << 0.01 by log-rank test), and there were 3 deaths due to viral infections (p = 0.08 by Fisher's exact test). Groups were similar in terms of immunosuppression and renal function during treatment, and none of the recipients developed leukopenia. We conclude that ganciclovir prophylaxis is well tolerated and appears to have considerable efficacy for prevention of CMV infections in pulmonary transplant recipients.