Chronic Rejection - 6

Time-related changes in pulmonary function after conversion to tacrolimus in bronchiolitis obliterans syndrome -J. Cairn MBBS, PART 2

Discussion - This study has defined the range of clinical responses of lung transplant patients to conversion from cyclosporine- to tacrolimus-based immunosuppression after diagnosis of BOS. The majority of patients (n = 19) showed a reduction in the rate of deterioration of lung function. Non-response to conversion to tacrolimus was associated with a poor prognosis as borne out by a trend in the actuarial survival data, although the comparison between responder and non-responder sub-groups did not achieve statistical significance. Overall, and also in the responder sub-group, conversion to tacrolimus led to an improvement in the rate of decline of both FEV1 and FEF25%-75%, which is probably a more direct measurement of small airway function. This is comparable to the results of previous smaller studies such as that of Kesten and co-workers, who found that 7 of 12 patients had a stable FEV1 by 6 months and that the median monthly rate of decline of absolute FEV1 was 5.3% on cyclosporine and 1.1% after conversion to tacrolimus (p < 0.005). Ross et al. showed a significant reduction in the rate of decline of FEV1 after conversion from cyclosporine to tacrolimus in 10 patients with histologically confirmed obliterative bronchiolitis. The change in FEV1 per month over the previous 6 months while on cyclosporine was -0.687 ± 0.221 liter/month compared with +0.03 ± 0.033 liter/month after conversion to tacrolimus (p = 0.037).[13] Revell et al. demonstrated significant reductions in the rates of decline of both FEV1 (pre-conversion -70.5 ± 137 ml/month vs -6.53 ± 18.6 ml/month at 12 months post-conversion; p = 0.02) and FEF25%-75% (pre-conversion -234 ±194 ml/s per month vs 23 ± 14.8 ml/s per month at 12 months post-conversion; p < 0.001) in a series of 11 patients with BOS. This study design examined lung function at 6 monthly intervals.Our study included the largest series of patients so far and has also attempted to examine the effect of tacrolimus conversion on pulmonary function for a follow-up period of 12 months, which was divided into smaller 3 monthly intervals, and therefore giving more data points than the study by Revell et al. In addition to FEV1, changes in small airway function, as represented by FEF25%-75%, were examined. The changes in the median rate of decline of FEF25%-75% mirrored those of the FEV1, and in the majority of patients tacrolimus had a sustained effect on reducing the rate of decline in pulmonary function up to 12 months after conversion. This study also attempted to compare pre-, peri- and post-operative variables in patients who responded to tacrolimus with a stabilization in their lung function vs those who did not and who continued to show a decline in FEV1 and FEF25%-75%. The actuarial survival of 2 sub-groups (responders and non-responders) was also compared. Our study did not demonstrate any significant relationship between the number of preceding acute rejection episodes and the subsequent response to tacrolimus.Smith et al. found that there was a significant correlation between the development of anti-HLA antibodies and BOS, and the development of these antibodies within the first 2 years after transplantation was associated with a significantly lower actuarial survival. This hints at the possibility that the development of BOS within 2 years after transplantation may be associated with a poorer prognosis. In the present study, one could speculate that those patients who did not respond to augmented immunosuppression by conversion from cyclosporine to tacrolimus may have had a more aggressive form of BOS, although this had not been demonstrated previously. Therefore, in the present study, the intervals between both the dates of transplantation and the dates of BOS diagnosis and tacrolimus conversion were calculated and compared statistically between the two sub-groups. This was designed to assess whether the non-responder sub-group developed BOS earlier than the responder sub-group. Although there was a trend toward longer mean and median intervals between transplantation and either the date of diagnosis of BOS or the date of conversion to tacrolimus for the responder sub-group compared with non-responders in this small study, this trend did not achieve statistical significance. A larger study might have proved more illuminating.A randomized, controlled trial comparing tacrolimus rescue therapy to a group of patients in whom maintenance immunosuppression was not changed would be difficult to perform. The ethics of withholding tacrolimus from patients with the diagnosis of BOS and continuing with a higher target trough level of cyclosporine as an alternative would indeed be problematic in a randomized trial because the use of tacrolimus as a "rescue" therapy is now an established practice at some transplant centers, including our own, and seems to be useful to the majority of patients.Primary immunosuppression trials comparing cyclosporine with tacrolimus in lung transplant recipients have shown fewer acute rejection episodes in patients taking tacrolimus. Keenan et al. showed a trend toward less acute rejection in the tacrolimus group, where there were 1.09 acute rejection episodes per 100 days in the cyclosporine group vs 0.85 in the tacrolimus group (p = 0.07). The incidence of obliterative bronchiolitis was greater in the cyclosporine group (38%) vs the tacrolimus group (21.7%) (p = 0.025). The overall incidence of bacterial infections was greater in the cyclosporine group, but fungal infections were more frequent in the tacrolimus group. There was no significant difference in actuarial survival between the groups at 1 and 2 years, although there was a trend toward improved survival in the tacrolimus group. In view of the fact that biopsy-proven obliterative bronchiolitis was measured in this study, then an even greater reduction in the incidence of BOS for the tacrolimus group may have been found if this had been used as the alternative clinical end-point. Kur et al. found that there was a significantly better actuarial survival in the tacrolimus group compared with the group receiving cyclosporine as maintenance immunosuppression both at 6 months and at 1 year after transplantation. Acute rejection episodes per 100 days in the tacrolimus group were significantly fewer when compared with the cyclosporine group, but there was no significant difference in the incidence of OB. [Reichenspurner et al. demonstrated that the total number of acute rejection episodes and the number of refractory acute rejection episodes were lower in patients treated with tacrolimus and azathioprine compared with those taking cyclosporine and azathioprine. In addition, the actuarial survival was greater in the tacrolimus group. Tacrolimus and cyclosporine (after binding to FK-binding protein and cyclophilin, respectively) both inhibit calcineurin, which is responsible for calcium-dependent signal transduction, thereby preventing lymphokine production from helper T cells and cytotoxic T-cell generation. Cyclosporine, however, also promotes the production of the pro-fibrotic molecule, transforming growth factor (TGF)-. Previous studies have demonstrated that tacrolimus is 100 times more potent than cyclosporine in vitro in suppressing proliferative responses in murine and human mixed lymphocyte reactions, and that there is a 10-fold increase in potency for in vivo models of cell-mediated and humoral immunity.This difference in potency and the absence of an effect on TGF- may account for the effectiveness of tacrolimus as a rescue treatment in BOS. Tacrolimus has also been found to be effective in the treatment of refractory or recurrent acute rejection in lung and heart transplant recipients. [31 and 32]The present retrospective study used patients as their own controls and therefore its importance is limited. The natural history of BOS is variable and therefore there may have been a sub-set of our patients who would have experienced a natural slowing in the deterioration of lung function without tacrolimus therapy. Further randomized studies are needed that can compare tacrolimus conversion with other forms of rescue therapy in terms of lung function, actuarial survival and adverse effects. In addition, further stratification of potential risk factors in a larger group of patients may aid in identifying sub-groups with a more favorable long-term outcome. The subsequent incidence of chronic rejection following an earlier conversion to tacrolimus in patients at high risk of developing BOS, such as after recurrent acute rejection, also warrants further investigation.In conclusion, conversion from cyclosporine- to tacrolimus-based immunosuppression is associated with a favorable response in the majority of patients with BOS. A reduction in the rate of decline in lung function following the introduction of tacrolimus has been demonstrated for a period of at least 12 months. (Source: The Journal of Heart and Lung Transplantation Volume 22, Issue 1 , January 2003, Pages 50-57)