tacrolimus and Bronchiolitis-Obliterans

Lung transplantation is a well-accepted treatment for people with most end-stage lung diseases. Although both tacrolimus and cyclosporin are used as primary immunosuppressive agents in lung transplant recipients, it is unclear which of these drugs is better in reducing rejection and death without causing adverse effects.. To assess the benefits and harms of tacrolimus versus cyclosporin for primary immunosuppression in lung transplant recipients.. We searched the Cochrane Renal Group's Specialised Register to 10 April 2013 through contact with the Trials Search Co-ordinator using search terms relevant to this review. We also searched Science Citation Index Expanded and the Transplant Library to 20 April 2013.. We included all randomised controlled trials (RCT) that compared any dose and duration of administration of tacrolimus versus cyclosporin as primary immunosuppressive treatment in lung transplant recipients. Our selection criteria required that all included patients received the same additional immunosuppressive therapy within each study.. Three authors extracted data. For dichotomous data we used risk ratio (RR) and used mean difference (MD) for continuous data, each with 95% confidence intervals (CI). Methodological components of the included studies were used to assess risk of systematic errors (bias). Trial sequential analysis was used to assess risk of random errors (play of chance).. We included three studies that enrolled a total of 413 adult patients that compared tacrolimus with microemulsion or oral solution cyclosporin. All studies were found to be at high risk of bias. Tacrolimus seemed to be significantly superior to cyclosporin regarding the incidence of bronchiolitis obliterans syndrome (RR 0.46, 95% CI 0.29 to 0.74), lymphocytic bronchitis score (MD -0.60, 95% CI -1.04 to -0.16), treatment withdrawal (RR 0.27, 95% CI 0.16 to 0.46), and arterial hypertension (RR 0.67, 95% CI 0.50 to 0.89). However, the finding for arterial hypertension was not confirmed when analysed using a random-effects model (RR 0.54, 95% CI 0.17 to 1.73). Furthermore, trial sequential analysis found that none of the meta-analyses reached the required information sizes and cumulative Z-curves did not cross trial sequential monitoring boundaries. Diabetes mellitus occurred more frequently among people in the tacrolimus group compared with the cyclosporin group when the fixed-effect model was applied (RR 4.24, 95% CI 1.58 to 11.40), but no difference was found when the random-effects model was used for analysis (RR 4.43, 95% CI 0.75 to 26.05). Again, trial sequential analysis found that the required information threshold was not reached and cumulative Z-curve did not cross the trial sequential monitoring boundary. No significant difference between treatment groups was observed regarding mortality (RR 1.06, 95% CI 0.75 to 1.49), incidence of acute rejection (RR 0.89, 95% CI 0.77 to 1.03), numbers of infections/100 patient-days (MD -0.15, 95% CI -0.30 to 0.00), cancer (RR 0.21, 95% CI 0.04 to 1.16), kidney dysfunction (RR 1.41, 95% CI 0.93 to 2.14), kidney failure (RR 1.57, 95% CI 0.28 to 8.94), neurotoxicity (RR 7.06, 95% CI 0.37 to 135.19), and hyperlipidaemia (RR 0.60, 95% CI 0.30 to 1.20). Trial sequential analysis showed the required information thresholds were not reached for any of these outcome measures.. Tacrolimus may be superior to cyclosporin regarding bronchiolitis obliterans syndrome, lymphocytic bronchitis, treatment withdrawal, and arterial hypertension, but may be inferior regarding development of diabetes. No difference in mortality and acute rejection was observed between patients treated with tacrolimus and cyclosporin. There were few studies comparing tacrolimus and cyclosporin after lung transplantation, and the numbers of patients and events in the included studies were limited. Furthermore, the included studies were deemed to be at high risk of bias. Hence, more RCTs are needed to assess the results of the present review. Such studies ought to be conducted with low risks of systematic errors (bias) and of random errors (play of chance).

Topics: Adult; Bronchiolitis Obliterans; Cyclosporine; Diabetes Mellitus; Graft Rejection; Humans; Hypertension; Immune Tolerance; Immunosuppression Therapy; Immunosuppressive Agents; Lung Transplantation; Middle Aged; Randomized Controlled Trials as Topic; Tacrolimus

Although significant gains have been made in improving lung function and survival in cystic fibrosis (CF), ultimately respiratory failure is the leading cause of mortality in these patients. For CF patients with end stage lung disease, lung transplantation is an option for treatment. The field of lung transplantation has progressed markedly in the last 20 years. Nonetheless it remains a technically complex and challenging procedure, and patients are at risk for numerous short term and long term complications. Potential transplant recipients must be physically and psychologically prepared for the arduous process involved in lung transplantation. This article will review the history of lung transplantation, indications for transplantation, surgical techniques, and complications of transplantation.

Topics: Bronchiolitis Obliterans; Cystic Fibrosis; Graft Rejection; Heart-Lung Transplantation; Humans; Lung Transplantation; Respiratory Insufficiency; Tacrolimus; Tissue Donors

Obliterative bronchiolitis (OB) or the clinical correlate bronchiolitis obliterans syndrome (BOS) is the main cause of late morbidity and mortality after heart-lung and lung transplantation. Although several risk factors for the development of OB/BOS have already been identified, very effective preventive therapy remains Utopian, although there has been much improvement in recent years. This paper attempts to summarize current experience in the medical treatment of OB/BOS, either by tackling the known risk factors for the development of OB/BOS or by changing the immunosuppressive drug regimen for treating established OB/BOS. The current treatment options, however, are rather anecdotal and mostly single-centre experiences. Therefore, multicentre studies are definitely needed to try to identify the most appropriate drug regimen either to prevent and to treat obliterative bronchiolitis/bronchiolitis obliterans syndrome.

Topics: Bronchiolitis Obliterans; Humans; Immunosuppressive Agents; Lung Transplantation; Mycophenolic Acid; Risk Factors; Syndrome; Tacrolimus

Chronic lung allograft dysfunction, which manifests as bronchiolitis obliterans syndrome (BOS), is recognized as the primary cause of morbidity and mortality after lung transplantation. In this study we assessed the efficacy and safety of two de novo immunosuppression protocols to prevent BOS.. Our study approach was a multicenter, prospective, randomized (1:1) open-label superiority investigation of de novo tacrolimus vs cyclosporine, with both study arms given mycophenolate mofetil and prednisolone after lung transplantation. Cytolytic induction therapy was not employed. Patients were stratified at entry for cystic fibrosis. Primary outcome was incidence of BOS 3 years after transplant (intention-to-treat analysis). Secondary outcomes were survival and incidence of acute rejection, infection and other adverse events.. Group demographic data were well matched: 110 of 124 tacrolimus vs 74 of 125 cyclosporine patients were treated per protocol (p < 0.01 by chi-square test). Cumulative incidence of BOS Grade ≥1 at 3 years was 11.6% (tacrolimus) vs 21.3% (cyclosporine) (cumulative incidence curves, p = 0.037 by Gray's test, pooled over strata). Univariate proportional sub-distribution hazards regression confirmed cyclosporine as a risk for BOS (HR 1.97, 95% CI 1.04 to 3.77, p = 0.039). Three-year cumulative incidence of acute rejection was 67.4% (tacrolimus) vs 74.9% (cyclosporine) (p = 0.118 by Gray's test). One- and 3-year survival rates were 84.6% and 78.7% (tacrolimus) vs 88.6% and 82.8% (cyclosporine) (p = 0.382 by log-rank test). Cumulative infection rates were similar (p = 0.91), but there was a trend toward new-onset renal failure with tacrolimus (p = 0.09).. Compared with cyclosporine, de novo tacrolimus use was found to be associated with a significantly reduced risk for BOS Grade ≥1 at 3 years despite a similar rate of acute rejection. However, no survival advantage was detected.

Topics: Adult; Bronchiolitis Obliterans; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; International Cooperation; Lung Transplantation; Male; Middle Aged; Outcome Assessment, Health Care; Prospective Studies; Risk Factors; Survival Rate; Syndrome; Tacrolimus; Treatment Outcome

Lung transplantation has evolved into a life-saving therapy for select patients with end-stage lung diseases. However, long-term survival remains limited because of chronic rejection. Sirolimus is beneficial in preventing cardiac rejection and may decrease rejection after lung transplantation.. To determine the potential benefit versus risk of sirolimus in lung transplantation.. We conducted a multicenter randomized, open label controlled trial comparing sirolimus (SIR) with azathioprine (AZA) in a tacrolimus-based immunosuppressive regimen in lung transplantation. The primary end point was the incidence of acute rejection at 1 year after transplantation between the two study groups.. One hundred eighty-one patients were randomized to be included in this study. At 1 year after transplantation, there was no significant difference in the incidence of grade A acute rejection between the two study groups. Similarly, the incidence of chronic rejection and graft survival was no different between the two study groups. Cytomegalovirus infection was decreased in the SIR arm compared with the AZA arm (relative risk, 0.67 [95% confidence interval, 0.55, 0.82]; P < 0.01). There was a higher rate of adverse events leading to early discontinuation of SIR (64%) compared with AZA (49%) during the course of this study.. Sirolimus, an mTOR inhibitor, did not decrease the incidence of acute rejection at 1 year compared with azathioprine in lung transplantation. These results differ from previous results in cardiac and renal transplantation and emphasize the need for multicenter randomized controlled trials in lung transplantation. Clinical trial registered with www.clinicaltrials.gov (NCT 00321906).

Topics: Azathioprine; Bronchiolitis Obliterans; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Lung Transplantation; Male; Middle Aged; Sirolimus; Tacrolimus; Time Factors

Immunosuppression therapy in lung transplantation (LTX) remains unsatisfactory due to a high incidence of infection and frequent acute rejection (AR), leading to early onset of the bronchiolitis obliterans syndrome (BOS). The long-term success of LTX is limited by BOS, associated with marked morbidity and mortality. The strongest risk factor for BOS is frequent AR. Decreasing frequent AR episodes might lead to improved long-term survival following LTX.. Despite the introduction of many novel agents, the basis of currently applied protocols remains a calcineurin inhibitor, that is, cyclosporine/tacrolimus (TAC). Eighty-two lung recipients received oral-only administered immunosuppression with oral TAC, mycophenolate mofetil (MMF) and intravenous (IV) methylprednisolone as introduction 2h prior to skin incision. Intra-operatively, patients received additional methylprednisolone prior to unclamping the pulmonary arteries. Postoperatively oral TAC/MMF and prednisolone were continued and trough levels closely monitored (target 8-12 ng ml(-1)). Pulmonary function tests were performed frequently and daily after discharge by means of a self-measuring device (daily forced expiratory volume in 1s (FEV(1))) as the major part of a close follow-up and monitoring programme. Trans-bronchial biopsies were rarely performed. Patient data were collected prospectively and stored in transplantation registries. LTX survival was analysed according to the Kaplan-Meier method.. The follow-up of the LTX patients through frequent ambulatory care unit visits and close monitoring of the immunosuppressive regimen and the medication response was 100% complete. The mean duration of observation per patient was 1.8 + or - 1.7 years (median 1.4, range: 0.0-6.4 years) and this study included 176.5 patient-related years of follow-up. The 1-, 3- and 5-year survival following LTX was 70%, 60% and 55%, respectively. Eight patients (10%) underwent high-dose intravenous (IV) bolus methylprednisolone treatment and taper for AR. Two additional patients developed BOS more than 4 years following LTX. The AR- and BOS-related mortality was 0% within the 7-year interval of LTX. Alterations in FEV(1) were associated with significant anastomotic airway and infectious complications, requiring frequent bronchoscopic interventions, stenting and laser therapy as well as frequent IV antibiotic treatment. The 30-day and in-hospital mortality of 19.5% was markedly related to primary graft failure and viral infection. Long-term survival was limited predominantly by cytomegalovirus (CMV) infection and sepsis.. Our results suggest that a standard immunosuppressive regimen of TAC and MMF orally administered and introduced prior to skin incision for LTX surgery and maintained long-term might reduce the incidence of acute and chronic rejection. Viral infections and not BOS seemed to be the limiting factor of long-term survival.

Topics: Acute Disease; Administration, Oral; Adult; Bronchiolitis Obliterans; Drug Therapy, Combination; Epidemiologic Methods; Female; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Postoperative Care; Preanesthetic Medication; Tacrolimus; Treatment Outcome

The optimal maintenance immunosuppressive regimen after lung transplantation is uncertain.. We conducted a randomized controlled trial of tacrolimus versus cyclosporine in combination with azathioprine and prednisone after lung transplantation. Ninety adults were randomized to tacrolimus (n = 44) or cyclosporine (n = 46). The primary end point was a composite of a cumulative acute rejection A score of 3 or higher, a cumulative lymphocytic bronchitis B score of 4 or higher, or the onset of bronchiolitis obliterans syndrome (BOS) stage 0-p.. Recipients randomized to cyclosporine were significantly more likely to develop the primary end point than those randomized to tacrolimus. During the study period, the primary end point developed in 39 of 46 cyclosporine subjects compared with 24 of 44 tacrolimus subjects (p = 0.002); acute rejection or lymphocytic bronchitis end points developed in 29 of 46 cyclosporine subjects compared with 18 of 44 tacrolimus subjects (p = 0.036). Furthermore, BOS stage 0-p was more likely to develop in the cyclosporine group than in the tacrolimus group, but this was not statistically significant (log-rank p = 0.1). In addition, there was a trend to a higher incidence of diabetes among those in the tacrolimus group, but there was no significant difference in graft survival or the total number of infections, or in the incidence of hypertension, chronic kidney disease, or cancer between the 2 groups.. Tacrolimus is associated with a lower burden of acute rejection and lymphocytic bronchitis and a trend to a greater freedom from BOS stage 0-p than cyclosporine after lung transplantation.

Topics: Adult; Azathioprine; Bronchiolitis Obliterans; Bronchitis; Cyclosporine; Diabetes Mellitus; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Postoperative Care; Tacrolimus

Previous studies have demonstrated that shifting immunosuppressive therapy from cyclosporine (CyA) to tacrolimus (FK) may arrest the decline in forced expiratory volume in 1 second (FEV(1)) during chronic rejection after lung transplantation. Exhaled nitric oxide (eNO) has been shown to be elevated during chronic rejection. We report the concomitant stabilization of FEV(1) and decrease in eNO after changing from CyA to FK therapy in patients with chronic rejection after lung transplantation.. We used a prospective design. The study included 10 lung transplant patients (5 men and 5 women), mean age 44 +/- 14 years at time of transplantation, with a progressive decline in FEV(1) that was attributed to chronic rejection. Four patients underwent heart-lung transplantation and 3 had a sequential single and 3 a single-lung transplantation. The switch from CyA to FK occurred at 36 +/- 23 months after transplantation (Time 0). The eNO was measured using a chemiluminescence analyzer, according to standardized European Respiratory Society (ERS) criteria.. At Time 0, there were 6 patients in bronchiolitis obliterans syndrome (BOS) Stage 0-p, with a mean decline in FEV(1) of 15 +/- 3%; 2 in BOS Stage 1; and 2 in BOS Stage 2. Compared with the best post-operative FEV(1), there was a progressive and significant decline until Time 0, from 2.56 +/- 0.9 liters to 2.03 +/- 0.94 liters (p = 0.0047). Thereafter, FEV(1) stabilized: 2.03 +/- 0.94 liters at Time 0 and 2.05 +/- 0.94 liters 6 months later (p = non-significant). Concomitantly, there was a gradual increase in eNO during the 6 months before Time 0, from 11.4 +/- 2.5 ppb at the time of best FEV(1) to 20.5 +/- 14.8 ppb at Time 0. After switching, there was a non-significant decline in eNO, from 20.5 +/- 14.8 ppb to 14.9 +/- 5.4 ppb. There was no significant difference in eNO levels between the patients in BOS Stage 0-p and patients in higher BOS stages at either timepoint in the study.. This study illustrates that a switch from CyA to FK can stabilize pulmonary function in lung transplant patients with chronic rejection. This stabilization of FEV(1) is accompanied by a decrease in eNO, indicating that this treatment shift can reduce inflammation of airways during the course of chronic rejection. Consequently, measuring eNO may be extremely valuable in guiding the treatment of chronic rejection after lung transplantation.

Topics: Adult; Breath Tests; Bronchiolitis Obliterans; Chronic Disease; Cyclosporine; Female; Forced Expiratory Volume; Graft Rejection; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Nitric Oxide; Prospective Studies; Tacrolimus

Topics: Adult; Bronchiolitis Obliterans; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Reoperation; Tacrolimus; Time Factors

The need for better immunosuppressive protocols after lung transplantation led us to investigate tacrolimus (Tac) in combination with mycophenolate mofetil (MMF) and steroids or cyclosporine (CsA) in combination with MMF and steroids in a prospective, open, randomized trial after lung transplantation.. Between September 1997 and April 1999, 50 lung transplant recipients were randomized to receive either Tac (n = 26) or CsA (n = 24) in combination with MMF and steroids. All patients underwent induction therapy with rabbit antithymocyte globulin (ATG) for 3 days. Freedom from acute rejection (AR), patient survival, infection episodes, and side effects were monitored.. There was no difference in patient demographics between the two groups. Six-month and 1-year survival was similar (84.6% and 73.1% in the Tac group vs 83.3% and 79.2% in the CsA group). Freedom from AR at 6 months and 1 year after lung transplantation was slightly higher in the Tac group (57.7% and 50% vs 45.8% and 33.3%, p = not significant [n.s.]), whereas the number of treated rejection episodes per 100 patient days in the Tac group was significantly lower (0.225 vs 0.426, p < .05). Four patients in the CsA group had to be switched to Tac. Two patients in the CsA group had to be retransplanted. Incidence of infections was similar in both groups with a trend toward more fungal infections in the Tac group (n = 7 vs n = 1, p = n.s.).. The combination of Tac and MMF seems to have slightly higher immunosuppressive potential compared with CsA and MMF. The effectiveness of Tac as a rescue agent is not paralleled with undue signs of overimmunosuppression.

Topics: Acute Disease; Adult; Aged; Bronchiolitis Obliterans; Chronic Disease; Creatinine; Cyclosporine; Drug Combinations; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Infections; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome

Topics: Azathioprine; Bronchiolitis Obliterans; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Heart-Lung Transplantation; Humans; Lung Transplantation; Patient Selection; Prednisolone; Tacrolimus

A prospective clinical trial was undertaken to compare the efficacy of tacrolimus (FK 506) versus cyclosporine as the primary immunosuppressive agent after lung transplantation.. Between October 1991 and May 1994, 133 single-lung and bilateral-lung recipients were randomized to receive either cyclosporine (n = 67) or tacrolimus (n = 66). The two groups were similar in age, sex, and underlying disease.. One-year and 2-year survival rates were similar in the two groups, although the trend was toward increased survival with tacrolimus. Acute rejection episodes per 100 patient-days were fewer (p = 0.07) in the tacrolimus group (0.85) than in the cyclosporine group (1.09). Obliterative bronchiolitis developed in significantly fewer patients in the tacrolimus group (21.7%) compared with the cyclosporine group (38%) (p = 0.025), and there was greater freedom from obliterative bronchiolitis over time for patients receiving tacrolimus (p < 0.03). Significantly more cyclosporine-treated patients (n = 13) required crossover to tacrolimus than tacrolimus-treated patients to cyclosporine (n = 2) (p = 0.02). The switch to tacrolimus controlled persistent acute rejection in 6 of 9 patients. The overall incidence of infections was similar in the two groups, although bacterial infections were more common with cyclosporine (p = 0.0375), whereas the risk of fungal infection was higher with tacrolimus (p < 0.05).. This trial demonstrates the advantage of tacrolimus in reducing the risk of obliterative bronchiolitis, the most important cause of long-term morbidity and mortality after lung transplantation.

Topics: Acute Disease; Adult; Bronchiolitis Obliterans; Cross-Over Studies; Cyclosporine; Female; Follow-Up Studies; Fungemia; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Lung Transplantation; Male; Middle Aged; Pneumonia, Bacterial; Prospective Studies; Risk Factors; Survival Rate; Tacrolimus

Obliterative bronchiolitis (OB) was a main cause of deterioration of long-term prognosis in lung transplant recipients after the first posttransplant year. Proinflammatory cytokine interleukin-18 (IL-18) strengthened both the natural immunity and acquired immunity and played an important role in organ transplantation. The roles of IL-18 in the occurrence, development, and drug treatment of OB remained unclear.. Small interfering RNA (siRNA) against mouse IL-18 (siRNA-IL-18) was used to silence IL-18 expression. Mouse heterotopic tracheal transplantation model was used to simulate OB. Recipient mice were divided into 5 groups (. The luminal obliteration rates of IL-18 of the siRNA-IL-18 group were significantly lower than those of the negative control group (. IL-18 could be a novel molecular involved in the occurrence, development, and drug treatment of OB.

Topics: Animals; Azithromycin; Basigin; Bronchiolitis Obliterans; Disease Models, Animal; Humans; Interferon-gamma; Interleukin-18; Lung Transplantation; Male; Matrix Metalloproteinase 8; Matrix Metalloproteinase 9; Mice; RNA, Small Interfering; Tacrolimus; Transplantation, Homologous; Treatment Outcome

Obliterative bronchiolitis (OB) is the major complication limiting the long-term survival of allografts after lung transplantation. In this study, we investigated the effect of tacrolimus (FK506) combined with GM6001，a matrix metalloproteinase (MMP) inhibitor， on the formation of OB using a mouse heterotopic tracheal transplantation model.. Syngeneic tracheal grafts were transplanted heterotopically from BALB/c mice to BALB/c mice. Allografts from C57BL/6 mice were transplanted to BALB/c mice. Isograft group, allograft group, allograft+FK506 group, allograft +GM6001 group and allograft+FK506 + GM6001 group was given respectively intraperitoneal injection of saline, saline, FK506, GM6001 and FK506 + GM6001 once a day. At 28 day after transplantation, OB incidence was determined by hematoxylin-eosin staining and the expressions of MMPs and cytokines were assessed using enzyme linked immunosorbent assay, immunohistochemical assays and western blot assay.. The tracheal occlusion rates of isograft group, allograft group, allograft+FK506 group, allograft+GM6001 group and allograft+FK506 + GM6001 group were 0, 74.1 ± 9.79%, 34.4 ± 6.04%, 40.3 ± 8.77% and 26.5 ± 5.73% respectively. There were significant differences between the latter two groups (P < .001). The serum MMP-8 and MMP-9 levels of allograft group were significantly higher than those of isograft group (P < .05) and had no significant decrease when treated by FK506. The serum MMP-8 and MMP-9 levels of allograft+FK506 + GM6001 group were significantly lower than those of allograft+FK506 group (P < .05). MMP-8 and MMP-9 protein expression in the grafts of allograft+FK506 + GM6001 group were lower than those of allograft+FK506 group verified by immunohistochemical staining and western blotting.. FK506 combined with GM6001 could alleviate tracheal obliteration in mouse heterotopic tracheal transplantation model, due to its inhibitory effect on MMPs.

Topics: Airway Obstruction; Animals; Bronchiolitis Obliterans; Dipeptides; Disease Models, Animal; Drug Therapy, Combination; Graft Survival; Humans; Lung Transplantation; Male; Matrix Metalloproteinase 8; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Postoperative Complications; Tacrolimus; Trachea; Transplantation, Heterotopic; Transplantation, Homologous

Calcineurin inhibitors are a commonly used immunosuppressive drug and over 80% of lung transplant (LTx) recipients use tacrolimus. Sustained-release tacrolimus (SRT) was developed as a once-daily formulation, resulting in slower release and reduction in peak concentration compared with twice-daily immediate-release tacrolimus (IRT). Previous reports indicate that SRT may carry fewer side effects than IRT; however, the impact of SRT in bronchiolitis obliterans syndrome (BOS) after LTx is unclear.. Our study objective was to evaluate the effect of SRT in BOS after LTx.. We investigated the effect of SRT for BOS among 75 LTx recipients who were alive in 2017 in our LTx program. All analyses were carried out using student t test or F test.. Thirty-five recipients took IRT, 32 recipients used SRT, 7 recipients used cyclosporine, and 1 patient who received bone marrow and a lung graft from the same donor did not use a calcineurin inhibitor. The most frequent reason for conversion of IRT to SRT was kidney dysfunction, followed by other IRT complications. Five recipients underwent conversion of IRT to SRT because of decline of forced expiratory volume in 1 second (FEV1) with fluctuation of the tacrolimus trough level. After induction of SRT, the fluctuation of the tacrolimus trough level was significantly reduced in 4 of 5 patients (P < .05). Before drug form conversion, the FEV1 in these 5 patients was significantly decreased; however, this exacerbation of FEV1 was attenuated after SRT induction (P < .05).. SRT appeared to stabilize decline of FEV1 in patients with BOS possibly due to reducing the fluctuation of tacrolimus trough blood concentration.

Topics: Adolescent; Adult; Bronchiolitis Obliterans; Calcineurin Inhibitors; Cyclosporine; Delayed-Action Preparations; Drug Administration Schedule; Female; Forced Expiratory Volume; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Respiratory Function Tests; Tacrolimus; Young Adult

Insults to the airway epithelium play a key role in constrictive bronchiolitis after lung transplantation, the typical hallmark of chronic rejection. Our hypothesis is that immunosuppressives might affect airway integrity.. A biculture of human bronchial epithelial cells and lung microvascular endothelial cells was exposed to immunosuppressives (serum through levels) for 24 hours or 4 days. Cytotoxicity, transepithelial electrical resistance (TEER), and permeability was measured after exposure to monotherapies and combination therapies. Apoptosis, oxidative stress, inflammation (IL-8), real-time polymerase chain reaction for epithelial-to-mesenchymal transition and tight junction proteins were assessed in exposed cells.. Mycophenolate mofetil (MMF) and combination therapies including MMF, at serum trough levels and higher, are toxic for the human bronchial epithelial cells after 4-day exposure. Moreover, already after 24 hours, TEER of cells exposed to MMF decreases and permeability increases. MMF did not induce apoptosis, oxidative stress, loss of tight junctions or production of IL-8 after 24 hours, but possibly induces epithelial-to-mesenchymal transition in epithelial cells. MMF was detectable at both sides of the biculture and was also present in bronchoalveolar lavage of lung transplantation patients. Other immunosuppressives were not toxic, neither changed TEER or permeability.. Our findings suggest that MMF is present in the airways of lung transplant patients and might affect the structural integrity of the airway, which needs further investigation and validation in the clinical setting.

Topics: Azathioprine; Bronchiolitis Obliterans; Cyclosporine; Dexamethasone; Endothelial Cells; Epithelial Cells; Epithelial-Mesenchymal Transition; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Inflammation; Interleukin-8; Lung; Lung Transplantation; Microcirculation; Mycophenolic Acid; Permeability; Tacrolimus; Tight Junctions

Bronchiolitis obliterans is a complication after allogeneic haematopoietic stem cell transplantation (HSCT). Management of bronchiolitis obliterans comprises intensive immunosuppression, but treatment response is poor. We investigated the effect of cyclosporine A (CsA), tacrolimus (FK506), methylprednisolone (mPRED), mycophenolate mofetil (MMF) and everolimus on the proliferation of primary lung myofibroblasts from HSCT patients with bronchiolitis obliterans syndrome (BOS). Cells were isolated from surgical lung biopsies of eight HSCT patients with BOS. Proliferation was assessed by [(3)H]-thymidine incorporation. Biopsies revealed constrictive bronchiolitis obliterans in three patients and lymphocytic bronchiolitis in five patients. CsA and FK506 significantly induced proliferation of myofibroblasts. mPRED and MMF caused a significant inhibition of proliferation, whereas everolimus had no effect. Costimulation with FK506, mPRED and MMF significantly inhibited proliferation. Serial pulmonary function tests over 12 months after lung biopsy and under triple therapy demonstrated that patients with lymphocytic bronchiolitis had a significant improvement in forced expiratory volume in 1 s (FEV1), whereas FEV1 of patients with bronchiolitis obliterans was unchanged. Our data demonstrate a pro-proliferative effect of calcineurin inhibitors on primary human lung myofibroblasts obtained from patients with BOS after HSCT. In contrast, based on the observed antiproliferative capacity of MMF in vitro, MMF-based calcineurin inhibitor-free treatment strategies should be further evaluated in patients with bronchiolitis obliterans after HSCT.

Topics: Adult; Bronchiolitis Obliterans; Calcineurin Inhibitors; Cell Proliferation; Cells, Cultured; Cyclosporine; Drug Therapy, Combination; Everolimus; Female; Forced Expiratory Volume; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lung; Male; Methylprednisolone; Mycophenolic Acid; Myofibroblasts; Sirolimus; Tacrolimus

Bronchiolitis obliterans syndrome (BOS) is a major complication of lung transplantation that is associated with poor survival. The International Society for Heart and Lung Transplantation, American Thoracic Society, and European Respiratory Society convened a committee of international experts to describe and/or provide recommendations for 1) the definition of BOS, 2) the risk factors for developing BOS, 3) the diagnosis of BOS, and 4) the management and prevention of BOS. A pragmatic evidence synthesis was performed to identify all unique citations related to BOS published from 1980 through to March, 2013. The expert committee discussed the available research evidence upon which the updated definition of BOS, identified risk factors and recommendations are based. The committee followed the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) approach to develop specific clinical recommendations. The term BOS should be used to describe a delayed allograft dysfunction with persistent decline in forced expiratory volume in 1 s that is not caused by other known and potentially reversible causes of post-transplant loss of lung function. The committee formulated specific recommendations about the use of systemic corticosteroids, cyclosporine, tacrolimus, azithromycin and about re-transplantation in patients with suspected and confirmed BOS. The diagnosis of BOS requires the careful exclusion of other post-transplant complications that can cause delayed lung allograft dysfunction, and several risk factors have been identified that have a significant association with the onset of BOS. Currently available therapies have not been proven to result in significant benefit in the prevention or treatment of BOS. Adequately designed and executed randomised controlled trials that properly measure and report all patient-important outcomes are needed to identify optimal therapies for established BOS and effective strategies for its prevention.

Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Azithromycin; Biopsy; Bronchiolitis Obliterans; Cyclosporine; Disease Management; Forced Expiratory Volume; Gastroesophageal Reflux; Graft Rejection; Humans; Immunosuppressive Agents; Lung; Lung Transplantation; Reoperation; Risk Factors; Tacrolimus; Tomography, X-Ray Computed

Bronchiolitis obliterans syndrome (BOS) is associated with lack of immunosuppression of T cell proinflammatory cytokines and increased T cell granzyme B. Repeated antigen-driven proliferation down-regulates T cell CD28. We hypothesized that down-regulation of CD28 and up-regulation of alternate co-stimulatory molecules (CD134, CD137, CD152 and CD154) on T cells may be associated with BOS. Co-stimulatory molecules, granzyme B, perforin and intracellular cytokines were measured by flow cytometry on T cells from stable lung transplant patients (n = 38), patients with BOS (n = 20) and healthy controls (n = 10). There was a significant increase in the percentage of CD4/28(null) and CD8/28(null) T cells producing granzyme B, interferon (IFN)-γ and tumour necrosis factor (TNF)-α in BOS compared with stable patients. Down-regulation of CD28 was associated with steroid resistance and up-regulation of CD134, CD137, CD152 and CD154 on CD4(+) T cells and CD137 and CD152 on CD8(+) T cells. There was a significant correlation between increased CD28(null) /CD137 T cells producing IFN-γ, TNF-α with BOS grade (r = 0·861, P < 0·001 for CD28(null) /CD137 IFN-γ/CD8) and time post-transplant (r = 0·698, P < 0·001 for CD28(null) /CD137 IFN-γ/CD8). BOS is associated with down-regulation of CD28 and up-regulation of alternate co-stimulatory molecules on steroid-resistant peripheral blood proinflammatory CD4(+) and CD8(+) T cells. Therapeutic targeting of alternate co-stimulatory molecules on peripheral blood CD28(null) T cells and monitoring response using these assays may help in the management of patients with BOS.

Topics: Adult; Bronchiolitis Obliterans; Case-Control Studies; CD28 Antigens; CD40 Ligand; Costimulatory and Inhibitory T-Cell Receptors; CTLA-4 Antigen; Cyclosporine; Female; Granzymes; Humans; Immunosuppressive Agents; Interferon-gamma; Lung Transplantation; Lymphocyte Activation; Male; Middle Aged; Perforin; Postoperative Complications; Receptors, OX40; T-Lymphocyte Subsets; Tacrolimus; Tumor Necrosis Factor Receptor Superfamily, Member 9; Tumor Necrosis Factor-alpha; Up-Regulation

Survival after lung transplantation is mainly limited by the development of chronic lung allograft dysfunction (CLAD). The aim of this study was to investigate if platelet inhibition by clopidogrel has an influence on the formation of obliterative bronchiolitis, the histopathological correlate to bronchiolitis obliterans syndrome, present in the majority of patients suffering from CLAD. C57Bl/6(H2(b) ) donor tracheas were orthotopically transplanted into CBA.J(H2(k) ). Mice received different doses of clopidogrel alone or in combination with tacrolimus or everolimus. Grafts were analyzed by histology and immunofluorescence method on postoperative days 15, 30 or 60. Cytokines were analyzed by real-time polymerase chain reaction on postoperative day 21 and alloantibodies by FACS. Mice treated with 20 mg/kg/day clopidogrel for 30 days showed reduced obliteration [34.40 ± 3.76% (20 mg/kg/day clopidogrel) vs. 49.92 ± 2.11% (control), n = 5, P < 0.05]. Platelet inhibition resulted in significant lower infiltration of T cells and macrophages, and we also found significantly lower expression of IL-12, IL-4, IL-6, TNF-α, TGF-β, PDGFβ, MCP1, P-/E-selectin, ICAM1 and CD40L after treatment with clopidogrel. Combination of 1 mg/kg/day clopidogrel and 0.05 mg/kg/day everolimus or 12 mg/kg/day tacrolimus revealed a synergistic effect. Humoral immunity as manifested by donor-specific alloantibody secretion was also impaired after treatment with clopidogrel. Here, we can show that platelet inhibition by clopidogrel as a single treatment and in combination with tacrolimus or everolimus reduced the development of fibrosis and obliteration in tracheal allografts.

Topics: Animals; Blood Platelets; Bronchiolitis Obliterans; Calcineurin Inhibitors; Clopidogrel; Cytokines; Everolimus; Gene Expression Regulation; Immunohistochemistry; Isoantibodies; Lung Diseases; Lung Transplantation; Macrophages; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Microscopy, Fluorescence; Models, Animal; Platelet Aggregation; Platelet Aggregation Inhibitors; Postoperative Complications; Sirolimus; T-Lymphocytes; Tacrolimus; Ticlopidine; Time Factors; TOR Serine-Threonine Kinases; Trachea

Topics: Bronchiolitis Obliterans; Graft Rejection; Humans; Immunosuppressive Agents; Lung Transplantation; Survival Analysis; Survival Rate; Tacrolimus

Topics: Adolescent; Adult; Antibodies, Monoclonal, Murine-Derived; Bronchiolitis Obliterans; Bronchodilator Agents; Fatal Outcome; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Immunosuppressive Agents; Macrolides; Male; Mycophenolic Acid; Prednisone; Rituximab; Tacrolimus; Transplantation Conditioning; Treatment Outcome

Topics: Adolescent; Adult; Antibody Specificity; Bronchiolitis Obliterans; Drug Therapy, Combination; Female; Graft Rejection; Histocompatibility Antigens Class I; Histocompatibility Testing; HLA Antigens; Humans; Immunoglobulin G; Immunosuppressive Agents; Isoantibodies; Longitudinal Studies; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Predictive Value of Tests; Tacrolimus; Young Adult

Long-term outcomes after lung transplantation remain poor mainly to the development of bronchiolitis obliterans syndrome (BOS). Currently, treatment options for BOS are very limited. Strategies to prevent and treat this complication include the use of aerosolized therapy with only cyclosporine used in patients to date. We describe the use of aerosolized tacrolimus in a lung transplant recipient with BOS. The patient demonstrated clinical improvement in functional capacity and oxygenation while receiving tacrolimus by nebulization. Further research is needed to study whether aerosolized tacrolimus is beneficial in lung transplant recipients with BOS.

Topics: Administration, Inhalation; Adult; Aerosols; Bronchiolitis Obliterans; Dyspnea; Female; Humans; Immunosuppressive Agents; Lung Transplantation; Nebulizers and Vaporizers; Respiratory Function Tests; Tacrolimus; Time Factors; Treatment Outcome

A 64-year-old woman underwent allogeneic peripheral blood-derived stem cell transplantation for acute lymphocytic leukemia. She complained of dyspnea and was admitted to hospital 116 days after transplantation. Because of positive serum testing for the Aspergillus antigen and antibody, and ground-glass opacity in the right upper lobe on high-resolution computed tomography (HRCT), we made a diagnosis of pulmonary aspergillosis and administered an antifungal agent. Although tests for the Aspergillus antibody became negative and the ground-glass opacities disappeared, her dyspnea persisted. Progressive bronchiectasis was seen on HRCT, predominantly in the lower lobes. A pulmonary function test showed mixed impairment. We made a diagnosis of bronchiolitis obliterans after chronic graft versus host disease (GVHD). Prednisolone and an increased dose of tacrolimus (FK506) were administered, but type II respiratory failure progressed and she died 2 months after admission. On HRCT, each lobe was graded for bronchiectasis using a scale: 0 = normal, 1 = less than 2 x the diameter of an adjacent pulmonary artery, 2 = 2 - 3 x the diameter of an adjacent pulmonary artery, and 3 = more than 3 x the diameter of an adjacent pulmonary artery. A total score was calculated by summing the scores of all the lobes (maximum 15). In this case, the total score increased rapidly from 0 to 13 in 2 months.

Topics: Bronchiectasis; Bronchiolitis Obliterans; Chronic Disease; Disease Progression; Fatal Outcome; Female; Graft vs Host Disease; Humans; Middle Aged; Peripheral Blood Stem Cell Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Respiratory Insufficiency; Severity of Illness Index; Tacrolimus; Tomography, X-Ray Computed; Transplantation, Homologous

The optimal maintenance therapy after lung transplantation remains to be established. The aim of this study was to analyse the impact of tacrolimus and mycophenolate mofetil (MMF) as first line immunosuppression on long-term survival and Bronchiolitis Obliterans Syndrome (BOS). From January 1996 through December 2006, all 155 recipients receiving tacrolimus and MMF as maintenance immunosuppression were included in this study. Tacrolimus and MMF was discontinued in 36 patients (23.2%). The overall survival rates were 91.6% at 6 months, 86.4% at 1 year, 74.9% at 3 years, 60.3% at 5 years and 32.4% at 10 years. The overall freedom from acute rejection was 74.6%, 63.2% and 59.4% at 1, 3, and 5 years respectively. The overall BOS-free survival was 95.6% at 1 year, 88.4% at 3 years, 69.5% at 5 years and 30.5% at 10 years. The development of BOS > or = 1 was associated with a significantly increased risk of death and reduced long-term survival. The combination of tacrolimus and MMF offers safe and reliable maintenance immunosuppression after lung transplantation. However, substantial improvements of long-term survival and freedom from BOS might only be achieved by a change in organ allocation policies and patient management beyond differential immunosuppressive protocols.

Topics: Bronchiolitis Obliterans; Female; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Survival Analysis; Tacrolimus

A retrospective review of pediatric lung transplant recipients at 14 centers in North America and Europe was conducted to characterize the epidemiology and the risk factors for cytomegalovirus (CMV) and to explore the impact of preventative antiviral therapy.. Data were recorded for 1 year posttransplant. Associations between CMV and continuous and categorical risk factors were assessed using Wilcoxon rank sum and chi-square tests, respectively. Associations between time to CMV and risk factors or survival were assessed by multivariable Cox proportional hazards models.. Within 12 months posttransplant, 172 of 577 subjects (29.8%) developed 218 CMV episodes (90 asymptomatic infection, 25 syndrome, and 103 disease). Forty-one subjects developed more than one episode of CMV. Donor or recipient CMV seropositivity was associated with increased risk of CMV episodes. Except for decreased prophylaxis in CMV D-/R- subjects, duration of prophylaxis did not vary by D/R serostatus. For CMV D+ subjects, not being on prophylaxis at the time of CMV episode increased the risk of CMV (D+/R+ hazard ratio 3.5, 95% confidence interval 1.4-8.4; D+/R- 1.9, 1.02-3.7). CMV was associated with increased mortality within the first posttransplant year among those with donor or recipient CMV seropositivity (hazard ratio 2.0: 95% confidence interval 1.1-3.6; P=0.024).. CMV remains a serious complication after pediatric lung transplant, and the impact of prophylaxis is complex.

Topics: Acute Disease; Bronchiolitis Obliterans; Child; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Europe; Female; Graft Rejection; Heart-Lung Transplantation; Humans; Immunosuppressive Agents; Incidence; Lung Transplantation; Male; Multivariate Analysis; North America; Retrospective Studies; Survival Analysis; Survivors; Tacrolimus

Obliterative bronchiolitis (OB) is the most prominent cause of morbidity and mortality among lung transplant patients. No effective treatment for OB exists, but preliminary clinical studies have suggested that a calcineurin inhibitor, tacrolimus, may delay the development of OB when compared with standard cyclosporine-based immunosuppression.. Using a murine tracheal transplantation model, we examined the effects of tacrolimus prophylaxis and treatment on the development of obliterative airway disease (OAD). Tracheal allografts were transplanted heterotopically from BALB/c to C57 black mice into a subcutaneous pouch. The mice received different doses of tacrolimus monotherapy, ranging from 0 to 3 mg/kg/day, subcutaneously initiated at 0 (prophylaxis), 7 (early treatment) or 14 (late treatment) days. We harvested the grafts 30 days after transplantation for histologic and immunohistochemical analyses.. We found that tacrolimus prophylaxis dose-dependently inhibited OAD, and that early treatment halts OAD progression and that late treatment delays progression. Syngeneic grafts showed no obliterative changes. Tacrolimus prophylaxis was associated with inhibition of recruitment of CD4+, CD8+ and interleukin-2R+ inflammatory cells into the allografts, suggesting a central role for interleukin-2 in the development of OAD. In addition, a dose-dependent correlation between epithelial necrosis and tracheal occlusion was observed, suggesting that epithelial injury is required for the development of OAD. When tacrolimus treatment was initiated at the time the obliterative lesion had already started to develop, it inhibited the progression of OAD significantly.. The findings from this study suggest that tacrolimus therapy is effective during the early stages of clinical OB.

Topics: Animals; Bronchiolitis Obliterans; Calcineurin Inhibitors; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Immunosuppressive Agents; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Regression Analysis; Tacrolimus; Trachea; Treatment Outcome

The purpose of this study was to determine the utility of post-transplant serum soluble CD30 levels as a biomarker for the development of the bronchiolitis obliterans syndrome (BOS) after lung transplantation during a tacrolimus/mycophenolate mofetil-based regimen.. Soluble CD30 (sCD30) concentrations were measured prior to transplantation and in 175 samples taken after transplantation in 7 patients developing BOS and 7 non-BOS patients closely matched for age, underlying diseases, follow-up and gender.. High pre-transplant sCD30 levels dropped significantly after lung transplantation, but in the post-transplant samples no differences could be detected between patients developing BOS or not, and no changes were found prior to or during the development of BOS.. After transplantation, sCD30 levels are consistently suppressed, but BOS is not prevented, indicating that sCD30 cannot be used as a biomarker to predict BOS after transplantation in the regimen employed.

Topics: Adult; Antigens, CD; Biomarkers; Bronchiolitis Obliterans; Emphysema; Female; Graft Survival; Humans; Immunosuppressive Agents; Informed Consent; Ki-1 Antigen; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Predictive Value of Tests; Pulmonary Disease, Chronic Obstructive; Tacrolimus

Bronchiolitis obliterans syndrome (BOS) continues to be the main factor limiting the long-term survival of lung transplant recipients. The objective of this study was to prospectively assess the impact of conversion from cyclosporine (CsA) to tacrolimus on lung function in patients who developed BOS while receiving CsA-based immunosuppressive therapy. A total of 79 patients with BOS were included in the study. Sixty percent of patients had stage II or III BOS according to the International Society for Heart and Lung Transplantation criteria. Mean time from transplantation was 30.4 +/- 21.9 months and all patients were on CsA therapy at enrollment in the study, with mean trough levels of 232.75 +/- 98.26 ng/mL. After conversion, tacrolimus trough levels were 11.0 +/- 3.6 ng/mL at 3 months and 9.0 +/- 3.4 ng/mL at 12 months. Sixteen deaths occurred during the first year postconversion, 56% of which were due to respiratory failure. Comparison of forced expiratory volume in 1 second (FEV(1)) preconversion versus postconversion showed a change in the slope of the FEV(1)-time curve. The slope of the preconversion curve was -0.44 versus a zero slope, whereas the slope of the postconversion curve was 0.005, with a statistically significant difference between both slopes. This change in slopes, which was also seen in FEV(1%), suggests that lung function loss closed after conversion from CsA to tacrolimus supporting this therapeutic strategy in lung transplant recipients with BOS treated with CsA.

Topics: Adult; Bronchiolitis Obliterans; Cyclosporine; Female; Forced Expiratory Volume; Humans; Immunosuppressive Agents; Lung Diseases; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Respiratory Function Tests; Retrospective Studies; Tacrolimus; Tissue Donors

Standard immunosuppression after lung transplantation includes calcineurin inhibitors, mycophenolate mofetil, and steroids. Long-term survivors of lung transplantation are often confronted with chronic kidney disease, by definition related to the intake of calcineurin inhibitors. Sirolimus has been increasingly proposed as an alternative immunosuppressive agent due to its absence of nephrotoxicity, which could be used in selected patients.. We prospectively administered sirolimus as an alternative to calcineurin inhibitors in 10 lung transplantation recipients with persistent drug nephrotoxicity. They were switched from tacrolimus to sirolimus. Four patients also had bronchiolitis obliterans syndrome. The conversion scheme consisted of an immediate stop of tacrolimus and an 6 to 8-mg loading dose of sirolimus, followed by 4 mg/d. After 5 days, the sirolimus dose was adjusted to maintain trough levels between 12 and 18 ng/mL or 6 and 12 ng/mL for combined sirolimus and tacrolimus. Patients were monitored for renal and graft function as well as clinical status.. A significant decrease in creatinine was observed after 1 week of treatment (P = .011). Azotemia decreased after 1 month, remaining stable (P < .01). Pulmonary function tests did not show significant modification from before sirolimus, inception in patients with or without bronchiolitis obliterans syndrome. There were seven infections. One patient died of complications related to bronchiolitis obliterans.. Sirolimus was a useful alternative immunosuppressant, allowing significant tacrolimus withdrawal in transplant recipients with renal impairment. Sirolimus administration allowed recovery of renal function with low morbidity; it was useful for rescue of chronic renal impairment after lung transplantation.

Topics: Bronchiolitis Obliterans; Creatinine; Humans; Immunosuppressive Agents; Lung Transplantation; Sirolimus; Survivors; Tacrolimus

CD4+CD25+ regulatory T (Treg) cells have been shown to play a role in allograft tolerance and their peripheral counts vary according to the degree of graft acceptance in lung transplant recipients (LTR). Recent studies demonstrate that certain drugs might modulate generation, expansion and activity of Treg cells. Aim of this study was to evaluate the effect of therapeutic regimens used in our institution on peripheral CD4+CD25(high)CD69- Treg cell numbers in a group of 51 LTR with stable clinical conditions. They were treated with standard immunosuppression: calcineurin inhibitor (CNI)+azathioprine (AZA)+steroids (n=28) or with CNI+mycophenolate mofetil (MMF)+steroids (n=11) or with CNI+steroids (n=12). These stable LTR were compared with age-matched healthy controls (n=35) and with 19 LTR who developed bronchiolitis obliterans syndrome (BOS) and were treated analogously. Stable LTR showed higher peripheral Treg cell counts with respect to age-matched healthy controls (59.9+/-31.8/mul versus 42.1+/-16.9/mul, respectively; p<0.05). This increase was detectable in all patients treated with CNI either in association with AZA or MMF. During these treatments a significant expansion of Treg cell counts was detectable during acute rejection (AR) episodes (86.03+/-26.6/mul during AR versus 36.34+/-7.6 before AR; p<0,05). Moreover, the development of BOS was associated to a significant decrease of Treg cell counts irrespective to the immunosuppressive regimen used. In conclusion, therapeutic regimens based on CNI seem to allow a certain degree of peripheral Treg cell expansion in stable LTR.

Topics: Adult; Aged; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Azathioprine; Bronchiolitis Obliterans; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Female; Forkhead Transcription Factors; Gene Expression; Graft Rejection; Humans; Immunosuppressive Agents; Interferon-gamma; Interleukin-2 Receptor alpha Subunit; Lectins, C-Type; Lung Transplantation; Lymphocyte Activation; Lymphocyte Subsets; Male; Middle Aged; Mycophenolic Acid; Steroids; T-Lymphocytes, Regulatory; Tacrolimus

The primary aim of this study was to assess the safety and efficacy in lung transplantation of an immunosuppressive regimen aimed at achieving sirolimus and tacrolimus concentrations of 6 to 10 microg/ml and 5 to 7 ng/ml, respectively.. We retrospectively identified 49 lung transplant recipients who were converted to an immunosuppressive regimen consisting of tacrolimus, sirolimus, and prednisone. Data collected included demographic information, laboratory work, episodes of rejection, bronchiolitis obliterans syndrome (BOS) grade, and adverse effects.. The most common reason for conversion to a sirolimus and tacrolimus regimen was BOS. The most common adverse effects were increased triglycerides (10%), leukopenia (8%), and skin rash (6%). Four patients (8%) experienced acute allograft rejection during the study period. We followed BOS grade for 1 year in 23 patients. Of these, BOS grade improved in 8, 13 patients remained unchanged, and 2 worsened. Eleven patients (22%) discontinued sirolimus because of adverse events.. An immunosuppressive regimen consisting of sirolimus and tacrolimus that aims to keep the trough drug concentrations at 6 to 10 microg/ml and 5 to 7 ng/ml, respectively, provides effective lung allograft protection while maintaining an acceptable side-effect profile. The use of this immunosuppressive combination may have a benefit with regard to BOS.

Topics: Biopsy; Bronchiolitis Obliterans; Bronchoscopy; Drug Therapy, Combination; Female; Graft Rejection; Humans; Hyperlipidemias; Immunosuppressive Agents; Lipids; Lung; Lung Transplantation; Male; Middle Aged; Retrospective Studies; Safety; Sirolimus; Tacrolimus; Treatment Outcome

The effectiveness of the novel immunosuppressive agent FK778 and of tacrolimus to prevent the development of obliterative airway disease (OAD) was investigated in an animal model.. Tracheae from Brown-Norway donors were heterotopically transplanted in the greater omentum of Lewis rats. Recipients were treated for 28 days with FK778 (5 or 20 mg/kg), tacrolimus (1 or 4 mg/kg) or combination regimens at varying doses (5 + 1 mg/kg, 10 + 2 mg/kg or 20 + 4 mg/kg). Grafts were harvested and processed for histologic and immunohistochemical evaluation. Lymphocyte surface antigen expression was quantified and in vitro smooth muscle cell (SMC) proliferation assays were performed.. In untreated recipients, very large amounts of infiltrating CD4+, CD8+ and ED1+ mononuclear cells were observed in the peritracheal region with epithelial loss and complete luminal obliteration. Granulation tissue consisted of alpha-actin-positive cells and collagen-rich fibrosis. FK778 and tacrolimus as well as combination regimens of both agents dose-dependently inhibited peritracheal infiltration and luminal obliteration. Only tacrolimus-treated recipients showed preserved luminal epithelial coverage with airway goblet cells, whereas, in animals that received FK778, no epithelium was found. Both agents equally suppressed in vivo lymphocyte CD25 expression. Only FK778-treated animals were completely free of adverse drug side effects. FK778 but not tacrolimus showed potent anti-proliferative effects on SMC in vitro.. Although both agents proved effective to prevent OAD development, histology revealed major differences. The anti-proliferative potency of FK778 on SMC may be an important mechanism of action. Combination regimens showed favorable drug interaction and allowed dose reduction of both agents to achieve maximal immunosuppressive efficacy.

Topics: Actins; Alkynes; Animals; Bronchiolitis Obliterans; Disease Models, Animal; Granulation Tissue; Immunosuppressive Agents; Isoxazoles; Lymphocyte Activation; Nitriles; Postoperative Complications; Rats; Rats, Inbred BN; Rats, Inbred Lew; Tacrolimus; Trachea

Dysregulated fibroblast proliferation is thought to play an important role in the progression of bronchiolitis obliterans (BO) after lung transplantation. Augmented immunosuppression is often used to treat BO. We investigated the effect of methylprednisolone (mPRED), cyclosporine A (CsA), tacrolimus (FK506), azathioprine (AZA), mycophenolate mofetil (MMF), and everolimus (rapamycin derivative [RAD]) on the proliferative capacity of fibroblasts cultured from transbronchial biopsies of lung transplant recipients.. Primary cultures of human lung fibroblasts were obtained from 14 transbronchial biopsies of lung transplant recipients. Subconfluent cells were serum starved for 24 hr followed by growth stimulation in the presence or absence of the respective drug in six concentrations ranging as follows: 0.01 to 100 mg/L for mPRED; 0.01 to 50 mg/L for CsA and AZA; 0.001 to 5 mg/L for FK506 and MMF; and 0.00001 to 1 mg/L for RAD. Proliferation was quantified by [3H]thymidine incorporation and direct cell count. A toxic drug effect was excluded by trypan blue.. Drug concentrations (mg/L) causing a 50% inhibition of fibroblast proliferation were mPRED 4; CsA 20; FK506 0.3; AZA 7; MMF 0.3; and RAD 0.0006. Drug concentrations (mg/L) causing inhibition of fetal bovine serum-induced proliferation were mPRED 60; CsA 45; FK506 3; AZA 35; MMF 1; and RAD 0.003.. RAD and MMF were the most potent antifibroproliferative drugs and were effective at concentrations achieved clinically, supporting their use for the treatment of patients with early BO. Our method holds promise as an in vitro model to assess the likely in vivo responses of human lung fibroblasts to specific immunosuppressive drugs.

Topics: Adult; Aged; Azathioprine; Bronchi; Bronchiolitis Obliterans; Cell Division; Cells, Cultured; Cyclosporine; Everolimus; Female; Fibroblasts; Humans; Immunosuppressive Agents; Infections; Lung Diseases; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Sirolimus; Tacrolimus

A retrospective study involving 13 institutions was performed to assess the efficacy of conversion from cyclosporine (INN: ciclosporin) to tacrolimus.. Data from 244 patients were analyzed. Indications for conversion were recurrent-ongoing rejection (n = 110) and stage 1 to 3 bronchiolitis obliterans syndrome (n = 134).. The incidence of acute rejection decreased significantly within 3 months after versus before the switch from cyclosporine to tacrolimus (P <.01). For patients with recurrent-ongoing rejection, the forced expiratory volume in 1 second decreased by 1.96% of predicted value per month (P =.08 vs zero slope) before and increased by 0.34% of predicted value per month (P =.32 vs zero slope) after conversion (P <.06). For patients with stage 1 to 3 bronchiolitis obliterans syndrome, a significant reduction of rejection episodes was observed (P <.01). In single transplant recipients a decrease of the forced expiratory volume in 1 second averaged 2.25% of predicted value per month (P <.01 vs zero slope) before and 0.29% of predicted value per month after conversion. Corresponding values for bilateral transplant recipients were 3.7% of predicted value per month (P <.01 vs zero slope) and 0.9% of predicted value per month (P = 0.04 vs zero slope), respectively. No significant difference in the incidence of infections within 3 months before and after conversion was observed.. Conversion from cyclosporine to tacrolimus after lung transplantation is associated with reversal of recurrent-ongoing rejection. Conversion for bronchiolitis obliterans syndrome allows short-term stabilization of lung function in most patients.

Topics: Acute Disease; Adult; Australia; Azathioprine; Bronchiolitis Obliterans; Canada; Chronic Disease; Cyclosporine; Drug Therapy, Combination; Europe; Female; Follow-Up Studies; Forced Expiratory Volume; Graft Rejection; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Incidence; Kidney; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Retrospective Studies; Tacrolimus; Time Factors; Treatment Outcome

Bronchiolitis obliterans syndrome (BOS) is a leading cause of morbidity and mortality after lung and heart-lung transplantation. Present treatment is directed at the augmentation of pharmacologic immunosuppression.. This study examines the effect of substituting cyclosporine with tacrolimus on the forced expiratory volume in 1 second (FEV(1)) and on the forced expiratory flow between 25% and 75% of vital capacity (FEF(25%-75%)) in 32 patients who developed BOS. The proportional rates of decline of FEV(1) and FEF(25%-75%) before and after treatment with tacrolimus were calculated. The actuarial survival of responders and non-responders to tacrolimus was compared. Pre-operative and post-operative factors were investigated to determine any difference between the 2 groups.. There were significant reductions in the rates of decline of FEV(1) and FEF(25%-75%) when the rates in the 3 months before conversion to tacrolimus were compared with subsequent rates at 0 to 3 months, 3 to 6 months, 6 to 9 months and 9 to 12 months after conversion. The rates of decline of FEV(1) and FEF(25%-75%) in the 3 months before conversion were 0.11 liters/month and 0.13 liters/s per month, respectively. This compares with the rates of decline for FEV(1) and FEF(25%-75%) for the 3 months after conversion to tacrolimus of 0.04 liters/month (p = 0.023) and 0.04 liters/s per month (p = 0.022), respectively. The actuarial survival at 1 year from the time of conversion to tacrolimus for the responder sub-group and the non-responder sub-group were 89.2% and 75%, respectively, and at 4 years after conversion were 61.3% and 56.3%, respectively (p = 0.92).. Tacrolimus rescue therapy is effective at stabilizing lung function in patients with BOS, and this effect is apparent up to 12 months after conversion from cyclosporine.

Topics: Bronchiolitis Obliterans; Cyclosporine; Forced Expiratory Volume; Heart-Lung Transplantation; Humans; Immunosuppressive Agents; Lung; Lung Transplantation; Spirometry; Tacrolimus; Time Factors

Standard cyclosporine-based immunosuppression is ineffective in the treatment of refractory acute rejection (RAR) and obliterative bronchiolitis (OB) that follows lung transplantation. The aim of this study was to evaluate the results of switching from cyclosporine to tacrolimus in the treatment of these situations. Nineteen patients entered the study. The indication for switching was OB in 11 patients and RAR in 8. Mean age was 41.3 +/- 13.1 years. In patients with RAR, the number of acute rejections was 1.5 +/- 0.7 and there were zero episodes per patient per 100 days before and after switching, respectively ( P = 0.02). There was no significant reduction of the decline of forced expiratory volume (FEV(1)) within 6 months after switching in patients with OB. We conclude that the conversion from cyclosporine to tacrolimus was associated with favourable results in the treatment of RAR. Further studies are required to assess the influence of this approach in the treatment of OB.

Topics: Acute Disease; Adult; Bronchiolitis Obliterans; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Tacrolimus

Topics: Bronchiolitis Obliterans; Drug Therapy, Combination; Follow-Up Studies; Forced Expiratory Volume; Humans; Immunosuppressive Agents; Lung Transplantation; Mycophenolic Acid; Postoperative Complications; Survival Rate; Tacrolimus; Time Factors

In cystic fibrosis (CF) patients, lung transplantation is the only way to improve both quality and length of life. Data in the literature show that, in 80% of the cases, mortality after lung transplantation in CF patients is due to infections.. We microbiologically monitored 34 patients subjected to bilateral lung transplantation in during 1996 to 1999 to ascertain whether a change in the bacterial species isolated from the lower respiratory tract took place that might have influenced the clinical conditions of the patients.. Our results show that the percentage of nonfermenting Gram-negative bacteria isolated from the lower respiratory tract remains high even in the posttransplantation phase. Nevertheless, the general clinical conditions of most of the patients were good and the three patients who died did not do as a consequence of an infection.. Lung transplantation constitutes a valid therapeutic choice for CF patients because the microorganisms that we isolated from the lungs of the patients in our study behave mostly as contaminants rather than as colonizers. However, the transplanted patients remain at risk and thus require constant microbiological surveillance.

Topics: Bronchiolitis Obliterans; Bronchoalveolar Lavage Fluid; Cyclosporine; Cystic Fibrosis; Follow-Up Studies; Gram-Negative Bacteria; Humans; Immunosuppressive Agents; Lung Transplantation; Oxygen Consumption; Sputum; Survival Rate; Tacrolimus

We studied serial lung function in 11 patients with bronchiolitis obliterans syndrome who were treated with tacrolimus conversion following lung or heart-lung transplantation. Our results show that tacrolimus conversion slows the decline of lung function in bronchiolitis obliterans syndrome. The attenuation continues for at least 1 year following conversion.

Topics: Biopsy; Bronchi; Bronchiolitis Obliterans; Cyclosporine; Disease Progression; Follow-Up Studies; Forced Expiratory Volume; Heart-Lung Transplantation; Humans; Immunosuppressive Agents; Lung Transplantation; Maximal Midexpiratory Flow Rate; Retrospective Studies; Spirometry; Statistics, Nonparametric; Syndrome; Tacrolimus

Topics: Biological Availability; Bronchiolitis Obliterans; Cyclosporine; Cystic Fibrosis; Follow-Up Studies; Heart-Lung Transplantation; Humans; Immunosuppressive Agents; Lung Transplantation; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors

The development of obliterative bronchiolitis is a common cause for failure of lung allografts. Fibrinogenesis can occur for a number of different reasons but some groups have suggested that cyclosporin A (CsA) and tacrolimus (FK506) have different effects on the cytokines which induce fibrinogenesis. We investigated the effect of tacrolimus and CsA in tissue culture and found that there was indeed a negative effect on human lung small airway epithelial cell proliferation by recombinant transforming growth factor-beta (TGF-beta), which was reversed by anti-TGF-beta. The same effect was seen with CsA at immunosuppressive concentrations, which was also reversed by anti-TGF-beta, whereas no such inhibition was seen with tacrolimus at immunosuppressive doses unless high concentrations were used. Free TGF-beta was confirmed as being elevated in the supernatant of cell culture wells with standard dose CsA as opposed to low dose CsA or tacrolimus using an ELISA assay.

Topics: Bronchiolitis Obliterans; Cells, Cultured; Cyclosporine; Humans; Immunosuppressive Agents; Lung; Lung Transplantation; Tacrolimus; Transforming Growth Factor beta

Topics: Animals; Bronchiolitis Obliterans; Cyclosporine; Fibrosis; Graft Survival; Immunosuppressive Agents; Male; Mucous Membrane; Rats; Rats, Inbred Lew; Rats, Inbred Strains; Regeneration; Tacrolimus; Trachea; Transplantation, Heterotopic; Transplantation, Homologous

Chronic lung allograft rejection manifested by sustained declines in lung function is the most common cause of late death after lung transplantation. Numerous strategies have shown variable results. We sought to evaluate the effect of FK506 (tacrolimus) on bronchiolitis obliterans syndrome (BOS) after lung transplantation.. A single-center open study was conducted of 15 patients whose treatment was converted to tacrolimus from cyclosporine. Of the 15, 12 patients had BOS characterized by sustained loses in lung function while receiving cyclosporine. Rate of decline of forced expiratory volume in 1 second (FEV1) for the 12 patients was calculated before and after administration of tacrolimus. Biochemical changes before and after conversion were compared for the entire group.. Median monthly rate of decline in FEV1 was significantly reduced after administration of tacrolimus (5.3% vs 1.1%; p = 0.002). Forced vital capacity did not change significantly. No subjects experienced at least a 10% improvement in FEV1. At least a 10% further decline in FEV1 was noted in five subjects, and seven subjects had no change (i.e., within 10% of baseline). A minor nonsignificant increase in creatinine occurred after administration of tacrolimus. Blood cell count, electrolytes, and liver enzymes remained unchanged. The median change in fasting blood glucose was +0.7 mmol/L (p = 0.02).. Although tacrolimus does not reverse changes in FEV1 with BOS, in this nonrandomized study it seemed to be associated with a decrease in the rate of decline in lung function and no significant sustained toxicity. Further studies are necessary to substantiate this observation.

Topics: Adult; Bronchiolitis Obliterans; Female; Follow-Up Studies; Forced Expiratory Volume; Graft Rejection; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Spirometry; Tacrolimus; Treatment Outcome

In a consecutive case series (level V evidence) involving 10 recipients of unilateral lung transplantation (LT) with bronchiolitis obliterans, in conjunction with Fujisawa protocol 93-0-003, the physiologic responses to FK 506 (tacrolimus) "rescue" immunosuppression were assessed. Recipients were 22+/-18 months post-LT and demonstrated progressive allograft dysfunction that was refractory to pulsed-dose methylprednisolone therapy. All recipients received induction immunosuppression with Minnesota antilymphocyte globulin (10 to 15 mg/kg/d) for 5 to 10 days, cyclosporine (CsA) (whole-blood Abbott TDX fluorescence polarization immunoassay (Abbott Inc, Abbott Park, IL)=600 to 800 ng/mL), azathioprine (2 mg/kg/d), and prednisone (tapered to 0.2 mg/kg/d). The "rescue" regimen consisted of oral FK 506 adjusted to maintain a whole-blood Abbott IMX microparticle enzyme immunoassay (Abbott Inc, Abbott Park, IL) of 10 to 15 ng/mL with an initial increase in prednisone (1.0 mg/kg/d) during conversion that was subsequently tapered to 0.2 mg/kg/d. Spirometry was performed monthly in accordance with accepted American Thoracic Society criteria. Recipients were classified in accordance with the International Society for Heart and Lung Transplantation (ISHLT) "Working Formulation for Standardization of Nomenclature and for Clinical Staging of Chronic Dysfunction in Lung Allografts" as stages Ib (n=2), IIb (n=4), and IIIb (n=4) upon entry to the protocol. The deltaFEV1/month relationships during CsA- and FK 506-based regimens were analyzed by linear regression and compared by signed rank test (p<0.05).. The deltaFEV1/month slopes were -0.0687+/-0.0221 and +0.0300+/-0.033 L/mo (mean+/-SEM) for CsA and FK 506, respectively (p=0.037). Although no significant spirometric improvement was noted in most recipients, no further decline in FEV1 occurred after conversion to FK 506. Recipients with less severe chronic dysfunction (ie, obliterative bronchiolitis [OB] stages Ib and IIb) stabilized their spirometric indexes at higher levels. Two recipients with OB stage IIIb died of hypercapnic respiratory failure at 6 and 8 months after conversion.. The deltaFEV1/mo slopes stabilized after FK 506 conversion. Earlier conversion may be beneficial in stabilizing FEV1 at a higher plateau. Significant economic impact may be anticipated with FK 506 compared to alternative cytolytic strategies for OB. However, multicenter prospective controlled investigations are necessary to further address the potential role of FK 506 after LT (level I evidence). Furthermore, the ISHLT "Staging of OB Syndrome" may have significant clinical implications vis-à-vis prognosis and potential therapies.

Topics: Bronchiolitis Obliterans; Chronic Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Lung Transplantation; Postoperative Complications; Prevalence; Societies, Medical; Tacrolimus; Treatment Outcome

Topics: Bronchiolitis Obliterans; Chronic Disease; Female; Graft Rejection; Heart-Lung Transplantation; Humans; Immunosuppression Therapy; Tacrolimus

Topics: Bronchiolitis Obliterans; Chronic Disease; Cyclosporine; Follow-Up Studies; Graft Rejection; Humans; Lung Transplantation; Randomized Controlled Trials as Topic; Tacrolimus

Topics: Adult; Bone Marrow Transplantation; Bronchiolitis Obliterans; Female; Graft vs Host Disease; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tacrolimus