Effects of Prophylactic Use of Sirolimus on Bronchiolitis Obliterans Syndrome Development in Lung Transplant Recipients

Effects of Prophylactic Use of Sirolimus on Bronchiolitis Obliterans Syndrome Development in Lung Transplant Recipients

Effects of Prophylactic Use of Sirolimus on Bronchiolitis Obliterans Syndrome Development in Lung Transplant Recipients Vikas Y. Sacher, MD, Debra Fer...

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Effects of Prophylactic Use of Sirolimus on Bronchiolitis Obliterans Syndrome Development in Lung Transplant Recipients Vikas Y. Sacher, MD, Debra Fertel, MD, Karan Srivastava, BS, Anthony Panos, MD, Dao Nguyen, MD, Tammy Baxter, MD, Shirin Shafazand, MD, and Si M. Pham, MD GENERAL THORACIC

Departments of Surgery, and Medicine, University of Miami, Miami; and Division of Pulmonology, Jackson Health System, Miami, Florida

Background. Sirolimus (SIR) has been shown to stabilize the lung function in lung transplant recipients with bronchiolitis obliterans syndrome (BOS). However, there is no long-term data on the prophylactic use of SIR in lung transplant recipients. This retrospective study examines the effects of SIR in the prevention of BOS. Methods. From 1999 to 2009, 24 lung transplant recipients whose maintenance immunosuppression regimen consisted of tacrolimus (Tac), mycophenolate mofetil (MMF) or azathioprine (AZA), and prednisone (Pred), were switched to Tac, SIR, and Pred at 1 year after transplantation. From these 24 patients, 5 developed side effects that necessitated the cessation of SIR within 1 year, while 19 patients tolerated long-term use of SIR. The clinical outcomes of these 19 patients (SIR group) were compared with 22 lung transplant recipients whose immunosupression regimen consisted of Tac, MMF or

AZA, and Pred from the time of transplant (MMF group). Survival rates and freedom from BOS were calculated by the Kaplan-Meier method. Results. The SIR group had a lower incidence of BOS and viral infection (p [ 0.05), and higher survival rates (p [ 0.004). The SIR group had lower levels of Tac and received less Pred. The incidences of acute rejection, carcinoma, hypertension, and diabetes were similar between both groups. Conclusions. Results from this study suggest that conversion to SIR 1 year after lung transplantation improves survival and decreases the development of BOS. Randomized studies with higher number of patients are needed to determine the prophylactic efficacy of sirolimus in preventing the development of BOS.

A

resultant T-cell stimulation. Calcineurin inhibitors have limited effectiveness in preventing chronic rejection (BOS). The antimetabolite drug MMF blocks de novo purine synthesis and inhibits B and T lymphocyte proliferation. Another class of immunosuppressive agents that has been used widely in solid organ recipients is the mammalian targets of rapamycin (mTOR) inhibitor that include sirolimus and everolimus. These drugs have been shown to be safe and effective immunosuppressive therapy in cardiac, liver, and renal transplantation [3, 4]. The mTOR inhibitors bind to mTOR and block interleukin-2 driven proliferation of T lymphocytes by inhibiting growth factor signal transduction [5]. Furthermore, the nephrotoxicity and neurotoxicity associated with cyclosporine and tacrolimus are potentially avoidable with the use of sirolimus (SIR) [6]. The antiproliferative characteristics and favorable side effect profile of sirolimus make it a promising drug for transplant patients. However, the enthusiasm for using sirolimus in lung recipients was dampened by bronchial anastomotic dehiscence when the drug was started immediately after transplant [7]. With delayed addition of sirolimus to the immunosuppressive regimen, sirolimus seems to be well tolerated in lung recipients.

lthough recent advancements have improved outcomes for lung transplant recipients, the postoperative phase is accompanied by complications that limit long-term survival, including acute rejection, infection, and bronchiolitis obliterans syndrome (BOS) [1]. Bronchiolitis obliterans syndrome is the clinical correlate of bronchiolitis obliterans, the pathologic entity that represents “chronic rejection” in pulmonary allografts. One year after transplant BOS is the most common cause of mortality, accounting for 20% to 29% of deaths in lung recipients [2]. The standard immunosuppressive protocols after lung transplantation consists of calcineurin inhibitors (cyclosporine or tacrolimus), antimetabolites (mycophenolate mofetil [MMF] or azathioprine [AZA]), and steroids. Calcineurin inhibitors act predominantly by blocking calcineurin-induced interleukin-2 (IL-2) production and

Accepted for publication July 22, 2013. Presented at the Poster Session of the Forty-ninth Annual Meeting of The Society of Thoracic Surgeons, Los Angeles, CA, Jan 26–30, 2013. Address correspondence to Dr Pham, 110 South Paca St, Ste 7th Flr, Baltimore, MD 21201; e-mail: [email protected].

Ó 2014 by The Society of Thoracic Surgeons Published by Elsevier Inc

(Ann Thorac Surg 2014;97:268–75) Ó 2014 by The Society of Thoracic Surgeons

0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2013.07.072

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Because of the antiproliferative effect, and its lower nephrotoxicity, it is postulated that sirolimus may reduce the incidence of BOS in lung recipients. Therefore, several lung transplant centers have incorporated sirolimus in the immunosuppressive regimen in a delayed fashion to avoid bronchial dehiscence. However, these studies are limited to only small retrospective studies [8–11] or prospective studies [12, 13] with short follow-up duration (3 years or less). Since 1999 we started to convert antimetabolites to sirolimus at 12 months after transplantation in lung recipients to prevent BOS. In the study reported herein, we examined whether the delayed conversion to sirolimus in a tacrolimus-based regimen as prophylactic treatment reduces the incidence of BOS in de novo lung or heart-lung transplant recipients. The patients in this study were followed for an average of 7 years.

Material and Methods Patient Population We retrospectively reviewed the charts of 72 patients who underwent lung or heart-lung transplantation between January 1999 and January 2009. Of these patients, 46 survived at least 1 year posttransplant with no evidence of BOS. Patients were divided into 2 groups on the basis of immunosuppressive regimens (Fig 1). Group 1 (or SIR group) consisted of patients receiving tacrolimus, MMF, or AZA and prednisone during the first year. At approximately 1 year (9 to 12 months) after transplantation, the immunosuppressive regimen of these patients was switched to tacrolimus, SIR, and prednisone. The other group (group 2 or MMF group) consists of patients receiving tacrolimus, MMF, or AZA and prednisone from time of transplant and throughout the follow-up period. The median follow up of the SIR group was 6.9 (3.3 to 11.7) years and for the MMF group was 4.8 (1.3 to 10.9) years. Included in the study are adult (18 years of age) patients who received single lung, bilateral lung, or heartlung transplant. The exclusion criteria included patients who underwent retransplantation and multiorgan transplantation (lung plus a solid organ other than heart), patients with previous solid-organ or bone marrow transplants, patients who died within 1 year after transplant, or developed BOS within the first year of transplant. The primary endpoints were the freedom from

BOS and patient survival rates. Secondary endpoints of the study were the incidences of acute rejection and adverse events (hyperlipidemia, hypertension, diabetes, malignancy, venous thromboembolism, anemia, leukopenia, thrombocytopenia, interstitial pneumonitis). The criteria for adverse events included the following: presence or absence of newly developed hypertension; presence or absence of hyperlipidemia (total cholesterol >239 mg/dL or serum triglycerides >399 mg/dL); presence of newly developed diabetes mellitus, renal insufficiency (serum creatinine >2 mg/dL), leukopenia (white blood count <4  109/L), and thrombocytopenia (platelet count <150  109/L); and presence of interstitial pneumonitis.

Immunosuppression Protocol Immunosuppression consisted of tacrolimus (Prograf; Astella USA, Deerfield, IL), MMF, or AZA, and steroids. During the first postoperative month, the dose of tacrolimus was targeted to maintain whole blood trough levels of 12 to 15 ng/mL. Tacrolimus dose was gradually reduced to achieve levels of 8 to 10 ng/mL after the first year. Methylprednisolone (Upjohn Pharmaceuticals, Kalamazoo, MI; 500 mg) was given intraoperatively before revascularization of each lung graft. Subsequently, a short course of steroid cycle was started on postoperative day (POD) 0, starting with 200 mg of methylprednisolone/ day administered intravenously in 4 divided doses. The dose of methylprednisolone was reduced gradually and converted to oral prednisone, (20 mg/day) on POD 6. Systematic reduction of prednisone dose (by 2.5 to 5 mg decrements) was initiated in all patients 3 months after transplantation if there was no significant rejection by transbronchial biopsy. Patients received either AZA (Imuran; Burroughs Wellcome, Research Triangle Park, NC) 2 mg/kg per day, or MMF (Cell-Cept; Roche Laboratories, Basel, Switzerland) 2 grams/day as the third immunosuppressive agents, starting on POD 0. After sirolimus was approved by the Food and Drug administration (FDA), some patients were converted from Imuran or MMF to sirolimus 1 year after transplant. In group 1, sirolimus (2 mg per day) was administered as prophylactic treatment 1 year after the transplant. The dose was adjusted to achieve a target sirolimus trough level between 6 and 11 ng/mL. After the sirolimus was started the tacrolimus dose was reduced to achieve the target trough level of 4 to 7 ng/mL [14]. In group 2, the target 12-hour trough level (whole blood) of tacrolimus was

Patients alive atleast 1 year with no BOS (n=46)

Within 1 year- MMF (21) AZA (3) After 1 year- SIR (n=24)

269

Within 1 year- MMF (18) AZA (4) After 1 year-MMF (n=22)

Fig 1. Study enrollment and inclusion in the retrospective study. (AZA ¼ azathioprine; BOS ¼ bronchiolitis obliterans syndrome; MMF ¼ mycophenolate mofetil; SIR ¼ sirolimus.)

GENERAL THORACIC

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Table 1. Drug Levels Variable

GENERAL THORACIC

Tacro level (ng/ml)  1 day posttransplant  2 year posttransplant  At last follow-up SIR level (ng/mL)  2 year posttransplant  At last follow-up Pred dose (mg/day)  1 day posttransplant  2 year posttransplant  Last follow-up MMF dose mg/day median (range)  2 year posttransplant  At last follow-up Pred ¼ prednisone;

SIR ¼ sirolimus;

Group 1 (SIR) (n ¼ 19)

Group 2 (MMF) (n ¼ 22)

p Value

12.64  2.3 8.6  2.2 6.8  1.7

12.35  1.7 10.4  1.5 9  2.6

0.65 0.006 0.002

9.1  2 7.7  1.8

– –

15.8  4.2 7.5  2.9 4.5  2.3

15.9  5.3 8.4  3.2 6.4  2.3

– –

1500 (1000–3000) 1000 (500–2000)

0.94 0.35 0.01

Tacro ¼ tacrolimus.

10 to 15 ng/mL during the first year and 9 to 12 ng/mL afterward (Table 1).

Monitoring and Treatment of Rejection Patients’ pulmonary status was regularly monitored through spirometry and full pulmonary function tests. All patients received surveillance bronchoscopy and transbronchial biopsy between PODs 14 and 21 unless clinical criteria warranted earlier intervention. Subsequently, surveillance biopsies were performed every 3 months in the first year. Thereafter, the biopsy was performed as needed based on symptoms and findings from pulmonary function tests. In addition, 3 to 4 weeks after treatment of rejection or cytomegalovirus pneumonia, transbronchial biopsies were performed.

Treatment of Acute Rejection Biopsies that were positive for acute rejection were graded as per the International Society of heart and Lung Transplant guidelines [15]. Grades A2 or greater were considered clinically significant. Acute rejection was treated with pulses of methylprednisolone (1 gram/day for 3 consecutive days). Follow-up bronchoscopy was performed 1 month later to verify resolution of rejection. Cytolytic therapy was used when the rejection was refractory to 2 to 3 courses of pulse steroids.

Infection Prophylaxis All patients at risk for cytomegalovirus (CMV) infection (donor or recipient serology positive for CMV) received prophylactic treatment of twice daily intravenous

Table 2. Demographic Data for Lung Transplant Recipients Variable Recipient age (yrs) Recipient sex (M:F) Donor age (years) Follow up (years) median (range) Ischemic time (minutes) Diagnosis (%) COPD IPF CF PPH Other CMV status Dþ/R Type of transplant Single lung Bilateral sequential lung Heart and lung

Group 1 (SIR) (n ¼ 19)

Group 2 (MMF) (n ¼ 22)

p Value

43  13 9:10 27  10 6.9 (3.3,11.7) 316  72

49  11 13:09 29  12 4.8 (1.3,10.9) 316  84

0.17

4 2 6 6 1 7

(21%) (10%) (32%) (32%) (5%) (37%)

2 (11%) 15 (78%) 2 (11%)

9 5 4 2 2 5

(42%) (22%) (18%) (9%) (9%) (23%)

0.40 0.009 0.98 0.20

0.50

2 (9%) 17 (77%) 3 (14%)

CF ¼ cystic fibrosis; CMV ¼ cytomegalovirus; COPD ¼ chronic obstructive pulmonary disease; Dþ/R ¼ donors had positive serology while recipients had negative serology for CMV; IPF ¼ idiopathic pulmonary fibrosis; MMF ¼ mycophenolate mofetil; PPH- primary pulmonary hypertension; SIR ¼ sirolimus.

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the determination of the baseline FEV1, the date of onset of BOS, and the grade of BOS. The two reviewers of pulmonary function tests to determine BOS stages were blinded to the treatment arms. We compared BOS grades before and after sirolimus therapy using the BOS criteria [1]. Spirometric variables, FEV1 and forced expiratory flow from the first to third quarters (25% to 75%), were obtained at each clinic visit.

Fig 2. Kaplan-Meier estimated freedom from bronchiolitis obliterans syndrome (BOS) till last follow-up. Patients who died, or lost to follow-up were censored.

ganciclovir at 5 mg/kg for at least 2 weeks after transplantation. Patients at high risk for CMV disease (donor positive/recipient negative) received prophylaxis with at least 4 weeks of intravenous ganciclovir and CMV hyperimmune globulin (CytoGam; CSL Behring, Kankakee, IL) at 150 mg/kg per dose for a total of 5 doses over 8 weeks. In addition, all patients were continued on oral ganciclovir for 6 months after completion of intravenous therapy. Patients also received prophylactic treatment with trimethoprim and sulfamethoxazole 3 times per week, or atovaquone if allergic to sulfa drugs, for pneumocystis carinii pneumonia. For antifungal prophylaxis, all lung recipients received inhaled liposomal amphotericin B or voriconazole for the first 6 months after transplantation.

Bronchiolitis Obliterans Syndrome All patients in the study followed up at our institution throughout their life. We followed outcome variables up until the last follow-up or the patient’s death. Two reviewers analyzed individual patient forced expiratory volume in the first second of expiration (FEV1) plots for

Continuous variables with normal distributions were reported as means with standard deviations. For continuous variables, both groups were compared using unpaired, 2-tailed t tests. Non-normal distributions were expressed as medians and ranges. For non-normal distributions, both groups were compared using Mann–Whitney tests (Graph pad Prism 5.0 software, San Diego, CA). Categoric variables were reported as the number and percent with the trait compared using Fisher exact tests. Kaplan-Meier estimates with log-rank tests were used for time-to-event analyses. For the endpoint of BOS, patients were followed until BOS developed or at last follow-up. For survival times, patients were followed until death or at last followup. The rate specific events (ie, acute rejections, infection episodes) were compared with both groups using 2-tailed unpaired t test. The rate of specific events was calculated by determining the number of events per year of study time for each subject. A p value of 0.05 or less was considered significant.

Results Demographics Of 46 lung recipients included in the study, 24 received sirolimus conversion. However 5 of these patients did not tolerate sirolimus for more than a month due to side effects (leukopenia, arthralgia, skin rashes, and gastrointestinal symptoms) and these patients were excluded from the analysis. Table 2 depicts the demographics of patients who received sirolimus (SIR group n ¼ 19) and those who did not (MMF group n ¼ 22).

Table 3. Incidence of Bronchiolitis Obliterans Syndrome (BOS) and Survival Data Group 1 (SIR) (n ¼ 19)

Variable a

No. of patients with BOS Freedom from BOS atb  3 year  6 year  9 year Survival rates atb  3 year  6 year  9 year a

Till last follow-up.

b

CI ¼ confidence interval;

Group 2 (MMF) (n ¼ 22)

Value

4

8

0.32 (95% CI: 0.20–1.6) Relative risk ratio: 0.57

100 81 61

76 57 38

0.05 (95% CI: 0.094–1) Hazard ratio: 0.31

100 89 67

76 50 37

0.004 (95% CI: 0.093–0.65) Hazard ratio: 0.25

Log-rank test. MMF ¼ mycophenolate mofetil;

SIR ¼ sirolimus.

GENERAL THORACIC

Statistical Analysis

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Primary Endpoints: Bronchiolitis Obliterans Syndrome and Survival Figure 2 and Table 3 show the frequency of patients remaining BOS free over time. Using the log-rank test, the group 1 (SIR group) had less incidence of BOS (p ¼ 0.05) compared with group 2 (MMF group). Group 1 had higher survival rates compared with group 2 (p ¼ 0.004) (Fig 3; Table 3).

Secondary Endpoints GENERAL THORACIC

Serious adverse events occurred commonly in both groups. There was a statistically significant higher incidence of hyperlipidemia in the sirolimus group (p ¼ 0.03). The incidence of diabetes mellitus, hypertension, anemia, leukopenia, thrombocytopenia, and skin malignancies (squamous cell and basal cell carcinoma) was not significantly different between the 2 groups. The SIR group had a higher incidence of venous thromboembolism than the MMF group (p ¼ 0.06) (Table 4). Two patients in the SIR group developed interstitial pneumonitis. The incidence of trend toward renal insufficiency was lower in group 1 but not statistically different. INFECTIONS. In both groups, the most common infectious agents for bacteria, viruses, and fungi were pseudomonas, CMV, and aspergillus, respectively. Bacterial and fungal infections were more common in group 2 (MMF group); however, there was no statistically significant difference between the 2 groups (p ¼ 0.06 and p ¼ 0.08, respectively). Viral infections were more common in the MMF group compared with the SIR group (p ¼ 0.05). However, the difference in CMV infections was not significant between the 2 groups (p ¼ 0.20) (Table 5). RENAL FUNCTION. The renal function (as reflected by serum creatinine) was more stabilized in the SIR group compared with the MMF group (Table 6). In the SIR group there was no difference in serum creatinine from initiation of sirolimus to the last follow-up. However, serum creatinine significantly increases over time in the MMF group (1.27  0.45 vs 1.70  0.98; p ¼ 0.02). ADVERSE

EFFECTS.

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Table 4. Incidence of Adverse Events After 1 Year Posttransplant Until Last Follow-Up Group 1 (SIR) (n ¼ 19)

Variable Hyperlipidemia Hypertension Diabetes Malignancy Venous thromboembolism Anemia Leucopenia Thrombocytopenia Interstitial pneumonitis Renal insufficiency a

11 7 3 4 3 3 3 2 2 3

Group 2 (MMF) (n ¼ 22)

(58%)a (37%) (16%) (21%) (16%) (16%) (16%) (11%) (11%) (16%)

5 5 6 4 5 4 5 7

(23%)a (23%) (27%) (18%) 0 (23%) (18%) (23%) 0 (32%)

p  0.05.

MMF ¼ mycophenolate mofetil;

SIR ¼ sirolimus.

ACUTE REJECTION. There was no significant difference between the 2 groups in the incidence of grade A equal to or greater than 2 rejection (Table 7). This is remarkable considering the fact that patients in SIR group had much lower level of tacrolimus and received less prednisone (Table 1).

Comment This retrospective study compares the outcomes of lung transplant recipients who received sirolimus with those who continue to receive MMF after 1 year of transplant in a tacrolimus-based immunosuppressive protocol. From an original cohort of 24 patients who received conversion to sirolimus, 5 patients suffered side effects and the drug was discontinued within less than 1 year. When compared with the MMF-treated group (n ¼ 22), patients who tolerated long-term use of sirolimus (n ¼ 19) had better survival rates, lower incidence of BOS, better renal function, and lower incidence of viral infection. However, they have higher incidence of hyperlipidemia, and a trend to higher incidence of thromboembolism (p ¼ 0.06). The incidences of acute rejection, carcinoma, hypertension, and diabetes were similar between both groups. The most notable finding is the difference in the long-term Table 5. Viral Infection Data Type of Infection

Fig 3. Kaplan-Meier estimated probability of overall survival till last follow-up. Patients lost to follow-up were censored. (MMF ¼ mycophenolate mofetil.)

All viral infections  No. of patients  No. of infections  Rate per patient per year CMV infections  No. of patients  No. of infections  Rate per patient per year CMV ¼ cytomegalovirus; sirolimus.

Group 1 (SIR) Group 2 (MMF) (n ¼ 19) (n ¼ 22) p Value 10 (53%) 19 0.13  0.15

16 (73%) 25 0.29  0.32

0.05

6 (32%) 8 0.06  0.11

10 (45%) 12 0.14  0.23

0.20

MMF ¼ mycophenolate mofetil;

SIR ¼

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Table 6. Renal Function Variable Serum creatinine  SIR  MMF Serum urea  SIR  MMF a

a

1 Year

Last Follow-Up

p Value

1.34  0.43 1.27  0.45

1.32  0.49 1.70  0.98

0.88 0.02

24.5  9 26  10.5

25  9 32.2  14.5

0.71 0.04

p  0.05 by paired 2-tailed t test.

MMF ¼ mycophenolate mofetil;

SIR ¼ sirolimus.

survival between the 2 groups. The 6-and 9-year conditional survival rates were 89% and 67% for the sirolimus group, and 50% and 37% for the MMF group (p ¼ 0.004). To our knowledge this is the only reported study in which long-term use of sirolimus (median follow-up ¼ 6.9 years) as a preventive measure is translated into lower incidence of BOS and improved survival in lung recipients. The results from our study differ from the previous prospective trial by Bhorade and colleagues [12]. In this multicenter randomized, open label prospective trial that consisted of 181 patients, sirolimus was compared with AZA in tacrolimus-based immunosuppressive regimen in lung recipients. Sirolimus was initiated 3 months after lung transplantation and patients were followed for 3 years. The authors reported no significant difference in freedom from BOS and patient survival rates at 1 and 3 years posttransplant between the 2 groups. The authors attribute the negative findings to the high discontinuation rate (64%) in the sirolimus arm and short duration of follow-up. In our study, 21% (5 of 24) patients did not tolerate sirolimus within 1 year and these patients were excluded from the analysis. The reason for the lower sirolimus discontinuation rate of our patients may be due to the fact that we delayed the use of the drug to 1 year posttransplant. At this time the use of other concomitant prophylactic medications that are toxic to bone marrow, such as valganciclovir and voriconazole, have been discontinued. Furthermore, the renal function also may be more stable at this time after the kidneys had time to recover from the perioperative stress along with the high level of tacrolimus in the early postoperative period.

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Long-term survival of lung recipients is jeopardized by the development of BOS, the most common cause of death [2]. Bronchiolitis obliterans syndrome is the clinical correlate of obliterative bronchiolitis, a pathologic entity characterized by mesenchymal cell proliferation surrounding the terminal bronchioles [1, 16]. Studies using animal models of chronic rejection in heart, kidney, and lung transplantation have shown that sirolimus inhibits pathologic mesenchymal cell proliferation [17–19]. Sirolimus also has important antiproliferative effects on adult lung fibroblasts. This could play an important role in preventing BOS and slowing down its clinical course once BOS is diagnosed [8–10, 20]. An earlier study by Villanueva and colleagues [21] reported that in lung recipients with documented BOS, a combination of sirolimus and tacrolimus decreases the progression of BOS. It suggests that sirolimus may be efficacious in the “active” phase of the disease. In our study we found that conversion to sirolimus after the first year after transplant reduces the incidence of BOS and improves survival in lung recipients. Improvement in renal function can be due to conversion to sirolimus or entirely due to tacrolimus dose reduction, but as the dose of tacrolimus was reduced renal function of SIR patients did not deteriorate as quickly as the control group. Other studies have reported similar findings [22–25]. Our study shows similar adverse effects of sirolimus as previously reported. The incidence of hyperlipidemia was higher in the SIR group compared with the MMF group. Hyperlipidemia has been reported in over 50% of patients receiving sirolimus [26]. A unique side effect of sirolimus, as compared with other immunosuppressive drugs, is thromboembolic event. As previously reported by Ahya and colleagues [13], we observed a trend toward a higher incidence of thromboembolic events in the SIR group. The molecular mechanism for this observation may be due to the fact that mTor inhibitors upregulate the expression of the prothrombotic gene plasminogen activator inhibitor-1 [27]. In our study, 2 patients in the SIR group developed interstitial pneumonitis, which resolved after discontinuing the drug. Sirolimus can cause pulmonary toxicity that includes interstitial pneumonitis, bronchiolitis obliterans organizing pneumonia, and alveolar hemorrhage [28]. Limitations of this study include the retrospective nature of the trial, small patient sample, and exclusion of patients who suffered side effects from sirolimus. While

Table 7. Incidence of Acute Rejection Episodes Grade A2 or Greater Variable Total grade A 2 acute rejection  No. of patients  No. of rejection episodes (Rate per patient per year) Grade A 2 acute rejection after 1 yeara  No. of patients  No. of rejection episodes (Rate per patient per year)

Group 1 (SIR) (n ¼ 19)

Group 2 (MMF) (n ¼ 22)

p Value

11 (58%) 0.12  0.14

9 (41%) 0.14  0.20

0.74

7 (37%) 0.07  0.11

5 (23%) 0.07  0.14

0.99

a

a

Until last follow-up.

MMF ¼ mycophenolate mofetil;

SIR ¼ sirolimus.

GENERAL THORACIC

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GENERAL THORACIC

retrospective analyses are less statistically rigorous than those collected in a prospective manner, we believe that this study provides important clinical information on the use of sirolimus in lung recipients, and may guide future studies in lung transplantation. Because of the retrospective nature of our study one should interpret the results reported herein with caution, and further prospective randomized trials are needed to validate our findings. In summary, our data suggest that judicious conversion to sirolimus 1 year after transplantation in lung recipients who received tacrolimus-based immunosuppression may reduce BOS and improve survival. Furthermore, a delayed use of sirolimus is well tolerated by a majority of lung recipients.

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INVITED COMMENTARY Lung transplantation has evolved into a life-saving therapy for patients with advanced lung diseases. Success rates after lung transplantation are largely due to advances in immunosuppressive therapies that have enabled transplant recipients to maintain Ó 2014 by The Society of Thoracic Surgeons Published by Elsevier Inc

lung allograft function with decreased acute and chronic rejection. However, it is unclear if any particular immunosuppressive therapy is better for decreasing rejection and improving survival after lung transplant. 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2013.08.034