A randomized trial of inhaled cyclosporine in lung-transplant recipients.

BACKGROUND: Conventional regimens of immunosuppressive drugs often do not prevent chronic rejection after lung transplantation. Topical delivery of cyclosporine in addition to conventional systemic immunosuppression might help prevent acute and chronic rejection events. METHODS: We conducted a single-center, randomized, double-blind, placebo-controlled trial of inhaled cyclosporine initiated within six weeks after transplantation and given in addition to systemic immunosuppression. A total of 58 patients were randomly assigned to inhale either 300 mg of aerosol cyclosporine (28 patients) or aerosol placebo (30 patients) three days a week for the first two years after transplantation. The primary end point was the rate of histologic acute rejection. RESULTS: The rates of acute rejection of grade 2 or higher were similar in the cyclosporine and placebo groups: 0.44 episode (95 percent confidence interval, 0.31 to 0.62) vs. 0.46 episode (95 percent confidence interval, 0.33 to 0.64) per patient per year, respectively (P=0.87 by Poisson regression). Survival was improved with aerosolized cyclosporine, with 3 deaths among patients receiving cyclosporine and 14 deaths among patients receiving placebo (relative risk of death, 0.20; 95 percent confidence interval, 0.06 to 0.70; P=0.01). Chronic rejection-free survival also improved with cyclosporine, as determined by spirometric analysis (10 events in the cyclosporine group and 20 events in the placebo group; relative risk of chronic rejection, 0.38; 95 percent confidence interval, 0.18 to 0.82; P=0.01) and histologic analysis (6 vs. 19 events, respectively; relative risk, 0.27; 95 percent confidence interval, 0.11 to 0.67; P=0.005). The risks of nephrotoxic effects and opportunistic infection were similar for patients in the cyclosporine group and the placebo group. CONCLUSIONS: Inhaled cyclosporine did not improve the rate of acute rejection, but it did improve survival and extend periods of chronic rejection-free survival. (ClinicalTrials.gov number, NCT00268515.).

Significance of a solitary perivascular mononuclear infiltrate in lung allograft recipients with mild acute cellular rejection.

BACKGROUND: Although a solitary prominent perivascular mononuclear infiltrate is diagnostic of mild acute rejection (A2) in lung allograft recipients, its significance is still poorly defined. We evaluated the significance of a solitary perivascular mononuclear infiltrate and its correlation with clinical outcome in lung allograft recipients. METHODS: Thirteen patients had mild acute rejection as diagnosed by the presence of a solitary perivascular mononuclear infiltrate. The patients were divided into 2 groups based on subsequent treatment: treated (Group 1) and non-treated (Group 2) patients. We analyzed the difference between the 2 groups according to clinical presentation, histologic parameters and outcome. RESULTS: Nine patients were women (69%), 4 were men (31%); 12 were white and 1 was African American. Ages at the time of biopsy ranged from 20 to 68 years, with a mean of 47.2 years and a median of 52 years. Eight had a history of single-lung transplant and 5 had a history of double-lung transplant. The most common reasons for transplantation were emphysema (n = 6) and cystic fibrosis (n = 3). Nine patients (65.4%) showed decreased rejection grade or no evidence of acute rejection (Group 1) after treatment. Four patients who were untreated had persistent multifocal mild or worsening moderate rejection on subsequent biopsy (Group 2). CONCLUSIONS: Treated and untreated patients with mild rejection based on a solitary perivascular infiltrate have similar clinical presentations and histologic characteristics. Solitary mononuclear infiltrates showed persistence or progression without therapy and therefore need to be treated as, not segregated from, the "usual" forms of mild acute allograft rejection.

Interleukin-10 production genotype protects against acute persistent rejection after lung transplantation.

BACKGROUND: Our previous studies demonstrated that cytokine gene polymorphisms are related to acute rejection in pediatric heart transplantation; a decreased tumor necrosis factor (TNF)-alpha production genotype combined with an increased or intermediate interleukin (IL)-10 production genotype was associated with the smallest incidence of acute rejection. The objective of this study was to determine whether cytokine genotypes TNF-alpha, IL-10, IL-6, interferon-gamma, and transforming growth factor beta were associated with acute persistent rejection after lung transplantation. METHODS: Cytokine genotyping was performed in 119 adult lung transplantation recipients who underwent surveillance transbronchial biopsies during their first year after transplantation. We categorized recipients with acute persistent rejection if they had 2 consecutive biopsy specimens at >/=Grade A2 despite anti-rejection treatment. We performed cytokine genotyping using the polymerase chain reaction-sequence specific primers technique, with a commercially available kit. RESULTS: We analyzed the IL-10 genotype in 116 patients. For the increased IL-10 production genotype, 7 of 20 patients (35%) were persistent rejecters. In comparison, 57 of 96 patients (59%) with intermediate or decreased IL-10 production genotype had acute persistent rejection (p = 0.046). For IL-10 haplotypes associated with intermediate IL-10 production, 30 of 45 patients with GCC/ACC haplotype (67%) had acute persistent rejection compared with 10 of 22 patients with GCC/ATA (45%). In the patients with intermediate IL-10 production, 17 of 22 (77%) with IL-10 GCC/ACC and IL-6 G/C had acute persistent rejection, whereas only 2 of 7 patients (29%) with IL-10 GCC/ATA and IL-6 G/G had acute persistent rejection (p = 0.018). CONCLUSIONS: In lung transplant recipients, the increased IL-10 production genotype protects against acute persistent rejection when compared with the intermediate or decreased IL-10 production genotypes. The intermediate IL-10 production genotype in lung transplant recipients can be differentiated into 2 haplotype responses, with the GCC/ACC haplotype associated more with acute persistent rejection. In lung transplant recipients, the immunomodulatory effects of IL-6 are differentiated in the G/C and G/G alleles in conjunction with IL-10 haplotypes, with G/C being associated with more acute persistent rejection in conjunction with the IL-10 GCC/ACC haplotype. Future pharmacogenomic models may incorporate these associations with acute persistent rejection in lung transplant recipients to formulate individualized therapeutic regimens.

Tacrolimus dosing in adult lung transplant patients is related to cytochrome P4503A5 gene polymorphism.

Tacrolimus is a potent immunosuppressive agent used in lung transplantation and is a substrate for both P-glycoprotein (P-gp, encoded by the gene MDR1) and cytochrome (CYP) P4503A. A previous study by the authors identified a correlation between the tacrolimus blood level per dose with CYP3A5 and MDR1 gene polymorphisms in pediatric heart transplant patients. The objective of this study was to confirm the influence of these polymorphisms on tacrolimus dosing in adult lung transplant patients. Adult lung transplant patients who had been followed for at least 1 year after lung transplantation were studied. Tacrolimus blood level (ng/mL) per dose (mg/day) at 1, 3, 6, 9, and 12 months after transplantation was calculated as [L/D]. DNA was extracted from blood. MDR1 3435 CC, CT, and TT; MDR1 2677 GG, GT, and TT; and CYP3A5*1 (expressor) and *3 (nonexpressor) genotypes were determined by PCR amplification, direct sequencing, and sequence evaluation. Eighty-three patients were studied. At 1, 3, 6, 9, and 12 months after the transplant, a significant difference in [L/D] was found between the CYP3A5 expressor versus nonexpressor genotypes (mean +/- SD of 1.49 +/- 0.88 vs. 3.11 +/- 4.27, p = 0.01; 1.23 +/- 0.82 vs. 3.44 +/- 8.97, p = 0.05; 1.32 +/- 0.96 vs. 3.81 +/- 6.66, p = 0.005; 0.95 +/- 1.19 vs. 3.74 +/- 5.98, p = 0.0015; and 0.45 +/- 0.2 vs. 3.76 +/- 6.75, p = 0.0001, respectively). MDR1 G2677T and C3435T genotypes had only minimal effects on [L/D] at 1 and 3 months after transplantation. This study confirms the relationship of CYP3A5 polymorphisms to tacrolimus dosing in organ transplant patients. CYP3A5 expressor genotypes required a larger tacrolimus dose to achieve the same blood levels than the CYP3A5 nonexpressors at all time points during the first posttransplant year. This was not uniformly true for MDR1. The authors therefore conclude that tacrolimus dosing in adult lung transplant patients is associated with CYP3A5 gene polymorphisms.

Pattern and predictors of early rejection after lung transplantation.

BACKGROUND: Most lung transplant recipients experience improvement in their underlying pulmonary condition but are faced with the threat of allograft rejection, the primary determinant of long-term survival. Several studies examined predictors of rejection, but few focused on the early period after transplantation. OBJECTIVES: To describe the pattern and predictors of early rejection during the first year after transplantation to guide the development of interventions to facilitate earlier detection and treatment of rejection. METHODS: Data for donor, recipient, and posttransplant variables were retrieved retrospectively for 250 recipients of single or double lung transplants. RESULTS: Most recipients (85%) had at least 1 episode of acute rejection; 33% had a single episode; 23% had recurrent rejection; 3% had persistent rejection; 13% had refractory rejection; and 14% had clinicopathological evidence of chronic rejection. Serious rejection (refractory acute rejection or chronic rejection) developed in 27% of recipients. Compared with other recipients, recipients who had serious rejection had more episodes of acute rejection (P = .004), and the first acute episodes occurred sooner after transplantation (P = .01) and were of a higher grade (P = .002). CONCLUSIONS: Recipients who experienced higher grades for their first episode of acute rejection (P = .03) and higher cumulative rejection scores (P = .004) were significantly more likely than other recipients to have serious rejection during the first year after transplantation.

Outcomes of lung volume reduction surgery followed by lung transplantation: a matched cohort study.

BACKGROUND: Lung volume reduction surgery (LVRS) has been demonstrated to provide symptomatic relief and to improve lung function in patients with end-stage emphysema. The goal of this study was to assess the additional morbidity associated with lung transplantation after LVRS for end-stage emphysema with regard to immediate postoperative outcomes, longitudinal spirometry, and survival rates compared to an age-, gender-, procedure-matched, and transplant time-matched cohort that had lung transplantation alone. METHODS: We compared the postoperative and long-term outcomes of a sequential procedure cohort to a matched cohort to assess the possible added post-transplant morbidity. RESULTS: Fifteen patients who underwent sequential LVRS (including 11 unilateral LVRS, 4 bilateral LVRS) and lung transplantation (ipsilateral in 7 and contralateral in 8) on average 28.1 +/- 17.2 months (median, 27.4 months; range, 3.7 to 61.7 months) later were assessed. No significant differences were noted in pretransplant demographics, post-transplant variables, longitudinal spirometric indices, or survival. A trend toward a lower pretransplant arterial carbon dioxide tension was apparent in the sequential procedure cohort. Group analysis revealed a significant increase in the number of patients requiring transfusion and in the total number of units transfused in patients undergoing ispsilateral transplantation after LVRS; a significant increase in the length of intensive care unit stay; and a trend toward an increase in the duration of hospital stay in patients undergoing lung transplantation within 18 months of LVRS. CONCLUSIONS: In appropriate candidates, LVRS bridged the time to transplantation by an average of 28.1 +/- 17.2 months (median, 27.4 months; range, 3.7 to 61.7 months) without significantly increasing post-transplant morbidity or mortality. Furthermore, bilateral LVRS bridged the time to transplantation to a greater extent than unilateral LVRS (34.9 +/- 29.8 months; median, 32.1 months versus 25.4 +/- 16.3 months; median, 22.3 months; p = 0.23).

Endobronchial metallic stent placement for airway complications after lung transplantation: longitudinal results.

BACKGROUND: In lung transplant recipients, bronchial stenosis (SB) and bronchomalacia (MB) result in obstructive airway disease and allograft dysfunction due to pulmonary infection. We hypothesized that endobronchial metallic stent placement for SB and MB would result in long-term improvement in respiratory function and rates of pulmonary infection. METHODS: We studied symptomatic lung transplant recipients with bronchoscopic evidence of proximal airway complications (SB or MB) and a synchronous decline in forced expiratory volume in 1 second (FEV1) of at least 10% in the 6-month period before intervention. Stent placement was the primary intervention for SB and all focal MB lesions and for recurrent or refractory SB lesions failing a single initial attempt at balloon dilation. FEV1 and rates of pulmonary infection were assessed in the 12-month interval before and after stent placement. Spirometric evaluation was performed at 3-month intervals and compared with spirometry at the time of stent placement. The rates of pulmonary infection, determined by the number of antibiotics prescribed, was determined before and after endobronchial correction. RESULTS: Thirty recipients underwent a total of 75 procedures (50 stent insertions and 25 balloon dilations). FEV1 improved significantly after stent placement compared with base line (1.29 +/- 0.43 L) as follows: 3 months, 1.45 +/- 0.50 L, p = 0.014; 6 months, 1.59 +/- 0.57 L, p = 0.002; 12 months 1.59 +/- 0.53 L, p = 0.006. The infection rate decreased from the 12-month period preceding stent insertion to the corresponding period after stent insertion (6.97/100 days +/- 6.33 versus 5.74/100 days +/- 7.76, p = 0.018). Recurrent SB occurred in 17.3%. No life-threatening complications occurred after stent placement and no deaths were attributed to stent malfunction or malposition. CONCLUSIONS: In lung transplant recipients with SB and MB, maintenance of airway patency by stent placement is safe and resulted in improvements in lung function and reduced pulmonary infection rates for up to 1 year after their insertion.