With a prevalence of 34% (55/162 at-risk recipients) and a mortality of 25% (14/55 affected recipients), obliterative bronchiolitis is the most significant long-term complication after pulmonary transplantation. Because of its importance, we examined donor-recipient characteristics and antecedent clinical events to identify factors associated with development of obliterative bronchiolitis, which might be eliminated or modified to decrease its prevalence. We also compared treatment outcome between recipients whose diagnosis was made early by surveillance transbronchial lung biopsy before symptoms or decline in pulmonary function were present versus recipients whose diagnosis was made later when symptoms or declines in pulmonary function were present. Postoperative airway ischemia, an episode of moderate or severe acute rejection (grade III/IV), three or more episodes of histologic grade II (or greater) acute rejection, and cytomegalovirus disease were risk factors for development of obliterative bronchiolitis. Recipients with obliterative bronchiolitis detected in the preclinical stage were significantly more likely to be in remission than recipients who had clinical disease at the time of diagnosis: 81% (13/15) versus 33% (13/40); p < 0.05). These results indicate that acute rejection is the most significant risk factor for development of obliterative bronchiolitis and that obliterative bronchiolitis responds to treatment with augmented immunosuppression when it is detected early by surveillance transbronchial biopsy.

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Infection and rejection remain the greatest threats to the survival of pulmonary allograft recipients. Furthermore, a relationship may exist between these events, because the occurrence of one may predispose to the other. By using multivariate analysis for repeated events, we analyzed the risk factors for bacterial, fungal, and viral infection, grade II or greater acute rejection, and death among 239 lung transplant recipients who received 250 allografts between January 1988 and September 1993. A total of 90 deaths, 491 episodes of acute rejection, and 542 infectious episodes occurred during a follow-up of 6 to 71 months. The hazard or risk patterns of death, infection, and rejection each followed an extremely high risk during the first 100 days after transplantation, a second modest risk period at 800 to 1200 days, and a lower constant risk. Infection and graft failure manifested by diffuse alveolar damage were the major causes of early death (< 100 days), whereas infection and chronic rejection were primary causes of later death after pulmonary transplantation. By multivariate analysis, cytomegalovirus mismatching risk for primary infection was the most significant risk factor for death, rejection, and infection. Absence of cytomegalovirus prophylaxis was also a risk factor for early and late death and late infection. Survival of recipients who received cytomegalovirus prophylaxis was significantly improved. Immunosuppression based on cyclosporine versus FK 506 was a risk factor for late death and late infection. Graft failure manifested by diffuse alveolar damage/adult respiratory distress syndrome was a significant risk for death late after transplantation. These data suggest the following: (1) The hazard for death, infection, and rejection after pulmonary transplantation appears biphasic; (2) lower survival is associated with ischemia-reperfusion lung injury represented by diffuse alveolar damage/adult respiratory distress syndrome; (3) cytomegalovirus mismatch, absence of cytomegalovirus prophylaxis, and development of cytomegalovirus disease are significant threats for death, rejection, and infection after pulmonary transplantation; (4) prevention of cytomegalovirus disease should improve survival by decreasing the prevalence of infection and rejection.

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)

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.

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.

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