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.

Empyema complicating successful lung transplantation.

OBJECTIVE: To assess the prevalence and etiology of empyema complicating successful lung transplantation. DESIGN: Retrospective review. SETTING: University medical center transplant service. PATIENTS: All recipients (n = 392) of single-lung, double-lung, and heart-lung transplantation between May 1984 and April 1997. RESULTS: Of the 392 transplant recipients, empyema was documented in 14 patients (3.6%) at a mean time (+/- SD) of 46 days after transplantation (range, 14 to 167 days). Of these 14 recipients with empyema, 4 recipients (28.6%) died of infectious complications related to empyema. Empyema was seen secondary to Gram-positive, Gram-negative, and saprophytic organisms; however, there was no predominance of a particular organism recovered from the empyemic fluid (chi2 = 0.53; p = 0.75). The development of empyema was not related to whether the transplant was performed secondary to a septic or nonseptic lung disorder (chi2 = 1.06; p = 0.67), nor was it related to the type of transplant procedure performed (ie, single-lung, double-lung, or heart-lung allografts; chi2 = 4.39; p = 0.30). CONCLUSION: Empyema, a relatively uncommon complication of lung transplantation, is not related to the type of allograft received or to whether the recipient had a septic or a nonseptic lung disorder. If empyema does occur, the mortality associated with this infection is substantial.

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.

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.

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.

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.

A comparison of ganciclovir and acyclovir to prevent cytomegalovirus after lung transplantation.

In an attempt to modify the sequelae of cytomegalovirus (CMV) infections after lung transplantation, 25 allograft recipients were randomized to either ganciclovir 5 mg/kg once a day 5 d/wk (Group G) or acyclovir 800 mg four times a day (Group A). All subjects received ganciclovir during postoperative Weeks 1 through 3, and they were then given either A or G regimens until Day 90. At termination of study enrollment, the cumulative incidence of all CMV infections (including seroconversions) was increased in Group A compared with that in Group G (75% versus 15%, p < 0.01), as was the incidence of overt CMV shedding and/or pneumonitis (50% versus 15%, p < 0.043). In comparison with those in Group G, subjects in Group A were also afflicted with an increased prevalence of obliterative bronchiolitis (OB) during the first year after transplantation (54% versus 17%, p < 0.033). Intravenous catheters for ganciclovir administration resulted in four complications among three of the subjects in Group G (23%). The short-term benefits of ganciclovir were ultimately limited, moreover, in that cumulative rates of CMV and prevalence of OB are now similar in both treatment groups after approximately 2 yr of observation. We conclude that prolonged ganciclovir prophylaxis decreases the early incidence of CMV and OB among lung transplant recipients, but these effects are of finite duration. Although CMV prevention appears to have considerable potential value in this population, definitive viral prophylaxis will require development of protracted or repeated treatment regimens, or longer-acting agents.

A new complication related to laser bronchoscopy in a single lung transplant recipient.

We report a nearly complete obstruction of the left mainstem bronchus by a fibrinomyxoid plaque about 12 h after laser resection of scar/granulation tissue at a left bronchial anastomosis 27 days after a left single lung transplant. The formation of this plaque was associated with respiratory failure. The plaque was removed by grasping the plaque with biopsy forceps inserted through a fiberoptic bronchoscopy that was placed into the left mainstem bronchus via an endotracheal tube while the patient was receiving manual ventilation under general anesthesia. The respiratory failure resolved with removal of the plaque. To our knowledge, this is a complication that has not been reported previously.

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.

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.

Rapid detection of cytomegalovirus pneumonia from lung lavage cells.

Because cytomegalovirus (CMV) is a common cause of fatal pneumonia in the immunocompromised host, a rapid and reliable method to confirm this diagnosis is essential. Bronchoalveolar lavage (BAL) has proved to be a rapid, safe, and sensitive method for the diagnosis of several forms of pneumonia in these patients, but its efficacy for confirming CMV pneumonia remains to be established. In this study, we compared the sensitivity and specificity of conventional viral culture, immunocytochemical staining, and cytological examination performed on cells recovered by BAL for establishing CMV as the cause of pneumonia in 71 BAL specimens from 56 immunocompromised patients. Pneumonia due to CMV was confirmed by stated criteria in 14 of these patients. Virus was isolated by culture in BAL specimens from all patients with CMV pneumonia (sensitivity 100%), but also in 17 specimens from patients who did not have CMV pneumonia (specificity 70%). On cytologic examination, CMV inclusions were found in 3 of the 14 specimens from patients with CMV pneumonia (sensitivity 21%) and also in 1 patient at risk for pneumonia but who did not fulfill the criteria (specificity 98%). Thus, a positive culture and positive cytology virtually confirmed CMV pneumonia, whereas a negative culture excluded it. Immunocytochemistry proved to be particularly useful when the culture was positive and cytology was negative. In this situation, specific labeling of CMV antigen by monoclonal antibody was found in 9 of the 11 patients with CMV pneumonia (sensitivity 82%). Thus, the absence of specific staining in BAL cells tended to exclude CMV as a cause of pneumonia in patients with positive cultures and negative cytologies.(ABSTRACT TRUNCATED AT 250 WORDS)