Immunosuppression in lung transplantation: a narrative review

Introduction

Lung transplantation has grown as a treatment option for patients with end stage lung disease. Unfortunately, in spite of improvement in survival rates over the last three decades, median survival for lung transplant recipients remains low at 6.7 years (1-3). Acute and chronic rejection are among the main challenges to graft function and overall survival in this population. Roughly 27% of patients experience an episode of treated acute rejection within the first post-transplant year, and bronchiolitis obliterans syndrome (BOS), one form of chronic lung allograft dysfunction (CLAD) continues to affect approximately 10% of patients each year (1). Restrictive allograft syndrome (RAS), the restrictive form of CLAD, is also being increasingly recognized (4). Immunosuppression is utilized to reduce rates of rejection, and can consist of induction therapy, in addition to maintenance therapy that typically includes a calcineurin inhibitor (CNI), antiproliferative agent, and corticosteroids. The need for induction therapy, the optimal choice of agents for induction and maintenance therapy, and the utility of adjunctive agents for preventing acute rejection or CLAD remains unclear. Consequently, practice patterns surrounding immunosuppression vary at different lung transplant centers. We will review current immunosuppressive medications that are available, the data behind their use in lung transplantation, and discuss adjunctive or novel therapies being used to improve lung transplant outcomes. We present the following article in accordance with the Narrative Review reporting checklist (available at https://ccts.amegroups.com/article/view/10.21037/ccts-21-42/rc).

Methods

Several PubMed searches were performed, using combinations of the keywords “lung transplantation, immunosuppression, induction, maintenance, basiliximab, anti-thymocyte globulin, alemtuzumab, belatacept, tacrolimus, cyclosporine, mycophenolate, azathioprine, sirolimus, everolimus, azithromycin, statins, and pirfenidone” from January 1985 to June 2022 (Table 1). Systematic reviews, randomized clinical trials, retrospective and cross sectional studies, case series, and some animal studies were considered for inclusion in this review. Papers were selected based on their relevance to the topic, and there were no language restrictions (Table 2).

Induction immunosuppression

Induction therapy utilizes intense immunosuppression in the perioperative period to reduce the risk of acute rejection that is mediated by a robust native T-cell response to the transplanted organ. Induction therapy may also aid with the reduction of doses of maintenance immunosuppression. Agents used target T-cells by causing T-cell depletion and/or disruption of T-cell activation and subsequent proliferation. The most commonly used induction agents are basiliximab, anti-thymocyte globulin (ATG), and alemtuzumab (Table 3) (1). High dose corticosteroids are often used intraoperatively, just before perfusion of the lung allograft, in order to reduce the risk of reperfusion injury. While the use of corticosteroids is not generally thought to be a part of induction therapy, there is likely some contribution to initial immunosuppression. Not all centers utilize induction therapy. However, most recent registry data from the International Society for Heart and Lung Transplantation (ISHLT) indicates that the proportion of patients receiving induction immunosuppression has steadily risen, with 80% of patients who underwent transplantation in 2017 receiving any form of induction (1). Slightly over 70% of patients who received induction therapy received an IL-2 receptor antagonist (IL-2RA) such as basiliximab, with other patients receiving ATG or alemtuzumab.

Basiliximab and daclizumab are chimeric murine/human monoclonal antibodies to the alpha subunit of the interleukin-2 (IL-2) receptor alpha chain, specifically binding to the CD25 antigen on activated T-lymphocytes (5,6). This prevents IL-2 mediated T-cell proliferation and differentiation, however, does not result in T-cell depletion. Daclizumab was removed from the US market in 2009 due to the development of several cases of severe, often fatal, inflammatory brain diseases, so basiliximab remains the only IL-2RA available for clinical use at this time. Basiliximab is administered intraoperatively or within two hours after transplantation, with a second dose typically given on post-operative day four. It is generally well tolerated, with no increase in adverse advents compared to placebo in clinical trials (3).

ATG is a polyclonal immunoglobulin preparation created from horses (equine ATG, ATGAM^©) or rabbits (rATG, Thymoglobulin^©) that contains antibodies against human T-cells (7,8). These antibodies act through Fc receptors and additional proteins on T-cell surfaces to deplete cytotoxic T-cells. ATG has also been shown induce B-cell apoptosis, modulate molecules that impact interaction of leukocytes and the endothelium, impact dendritic cell function, and induce regulatory T-cells and NK cells (9). ATG is administered using weight-based dosing starting on day one, often intraoperatively. Two to four additional doses are typically given every 24 hours, though single dose regimens have been described. Premedication with glucocorticoids, antihistamines and antipyretics is frequently used to prevent or reduce infusion related symptoms. Common adverse effects of ATG include chills, anxiety, abdominal pain, nausea, hyperkalemia, leukopenia, and thrombocytopenia. More serious adverse reactions, including infusion reactions, immune complex mediated glomerulonephritis, serum sickness, and cytokine release syndrome have also been reported (7,8).

Alemtuzumab is a recombinant DNA-derived humanized monoclonal antibody directed against the CD52 antigen present on all B- and T-lymphocytes (10). The use of this agent results in antibody-dependent cell lysis, and can cause sustained T-cell depletion for up to 3 years, and B-cell depletion for up to several months (11). Alemtuzumab also results in the depletion of monocytes, macrophages, and some subsets of dendritic cells, all of which express CD52, and impacts additional immune cell maturation resulting in a tolerogenic immune environment (12). Alemtuzumab is given as a single intravenous or subcutaneous injection at the time of organ reperfusion or immediately following transplantation. Common adverse reactions include infusion reactions, lymphopenia, infection, and secondary autoimmune disease, most notably thyroid disease. Less common, but more serious adverse reactions include cytokine release syndrome and prolonged pancytopenia (10).

Overall, an increasing proportion of patients undergoing lung transplantation receive induction therapy, with most patients using an IL2RA compared to ATG or alemtuzumab. For example, slightly over 70% of patients received an IL2RA for induction in 2017 (1). While data for induction therapy in lung transplantation consists largely of retrospective studies or small prospective trials, there is suggestion that induction reduces rates of acute rejection, and may improve long term survival (13-24). The most robust data in favor of induction can be found in retrospective trials of large transplant registries. Whitson et al. evaluated 12,858 patients from the United Network for Organ Sharing (UNOS) Registry, and found that induction therapy with basiliximab, alemtuzumab, or ATG improved overall survival when compared to no induction (median survival 71.3 vs. 63.2 months, P<0.001) (20). Additionally, a composite end point of treatment for rejection or death within the first year was significantly lower in the induction cohort compared to no induction (37% vs. 42%, P<0.001). Hachem et al. performed a retrospective cohort study of 3,970 patients from the ISHLT Registry and found that four year graft survival rates were better in patients who received induction with an IL-2RA or ATG compared to those who received no induction (64% and 60% vs. 57%, P=0.0067) (16). Rates of rejection were also decreased with IL-2RA and ATG therapy. There is some data suggesting that induction therapy may also have an impact on crucial long-term outcomes, such as CLAD. Furuya et al. reviewed 6,117 patients from the UNOS Registry, and found that induction therapy with basiliximab or alemtuzumab improved survival compared to no induction, and patients receiving alemtuzumab had a lower incidence of BOS at 5 years compared to no induction (22.7% vs. 55.4%, P<0.001) (19).

Prospective data regarding the use of induction therapy has been more mixed (13,25-29). Palmer et al. randomized 44 patients undergoing lung transplant to induction therapy with ATG or no induction, and found that grade II or greater acute rejection was less common in the ATG group (23% vs. 55%, P=0.03) (13). On the other hand, in a double blind, placebo-controlled trial of induction with ATG compared to no induction, Snell et al. found no difference in rates of death, graft loss, or acute rejection at one year. It is worth noting, however, that the protocol used in this study featured a single dose of ATG instead of a more traditional protocol utilizing additional doses of ATG on post-operative days 2–4 (29). Penninga et al. conducted a systematic review of six randomized controlled trials representing 278 patients who received either ATG, IL-2RA or muromonab-CD3, a monoclonal antibody to CD3 found on T-cells, and found no difference in mortality, acute rejection, or BOS with induction compared to no induction (28).

A major concern surrounding the use of induction therapy is the risk of complications, most notably post-transplant infection and malignancy. Some of the larger retrospective studies available did not evaluate these complications with induction, however, when reviewing the ISHLT Registry, Hachem et al. noted an increased incidence of early treated infection with IL-2RA and ATG when compared with no induction (45% and 43% vs. 38%, P<0.005) (16). In Furuya et al.’s UNOS registry review, a non-cytomegalovirus (CMV) infectious cause of death was more common in patients receiving alemtuzumab induction compared to basiliximab induction or no induction (29.9% vs. 20.8% vs. 22.3%, P<0.001). Alemtuzumab recipients were also more likely to have post-transplant lymphoproliferative disorder (PTLD) (4.5% vs. 0.4% basiliximab vs. 1.5% no induction, P<0.001) and other malignancies (9.0% vs. 6.2% basiliximab vs. 5.1% no induction, P<0.001) as a cause of death (19). However, the majority of retrospective studies have failed to demonstrate an increased risk of infection or malignancy with either IL-2RA, ATG, or alemtuzumab induction (14,15,18,22,30). Prospective studies have also failed to show an increased risk of these adverse outcomes with induction (13,26-29). Snell et al. noted a higher adverse event rate in patients treated with ATG, particularly high dose ATG, when compared to placebo, however, there was no significant difference in rates of infection or malignancy (29). In Penninga et al.’s systematic review, induction therapy was not associated with any increased risk of infection, pneumonia, CMV infection, PTLD or cancer when compared to no induction (28).

Data comparing induction agents is limited and primarily retrospective, but several studies seem to favor IL-2RAs compared to ATG (31-33). Ailawadi et al. reviewed 163 consecutive lung transplant patients at the University of Virginia who received either ATG or daclizumab, and found that patients that received daclizumab experienced significantly less acute rejection, BOS, and death compared to ATG (31). In a small study of 37 patients receiving ATG or basiliximab for induction, acute rejection rates were similar, however, survival was 20% higher in the basiliximab group (32). However, conflicting data does exist. In a review of 157 patients from Hachem et al., when comparing basiliximab to ATG, basiliximab patients were more likely to develop acute rejection of grade A2 or more, and were more likely to develop BOS at 2 years (36% vs. 26%, P=0.036) (34). Though alemtuzumab is not commonly used for induction therapy at this time, there is some data that suggests alemtuzumab may lead to reduced rates of acute rejection and potentially BOS (30,35-38). Shyu et al. reviewed 336 patients from a single center and found that five year patient and graft survival was significantly better in patients receiving induction with alemtuzumab (59%/59%) compared to ATG induction (60%/44%), daclizumab induction (44%/41%), and no induction (47%/46%) (30). Alemtuzumab patients also demonstrated improved 5-year freedom from acute cellular rejection (ACR), obliterative bronchiolitis, and BOS. Furukawa et al. retrospectively reviewed 807 lung transplants performed at a single center, of which 453 underwent alemtuzumab induction and 354 underwent basiliximab induction (38). Compared to basiliximab induction, alemtuzumab induction was associated with decreased rates of grade 3 primary graft dysfunction within 72 hours (19.9% vs. 29.9%, P=0.002), ACR in the first year (39.1% vs. 53.4%, P<0.001), and improved rates of survival at 5 years (64.1% vs. 52.3%, P<0.001). However, the basiliximab group had notably higher risk patients, with a significantly higher number of patients with a history of pulmonary fibrosis, HIV, hepatitis C, cancer, CMV positivity and CMV mismatch. In a prospective, open label, randomized controlled trial, Jaksch et al. randomized 60 patients to induction therapy with alemtuzumab or ATG, and found that alemtuzumab was associated with fewer episodes of ≥ A2 ACR within the first year compared to ATG (0 vs. 5, P=0.019) (36). There was no difference in survival, lymphocytic bronchiolitis, infection or BOS between the two groups. A meta-analysis by of six studies including 595 patients by Li et al. showed that alemtuzumab was associated with lower odds of ACR compared to ATG, and lower rates of acute rejection and infection when compared to basiliximab (39).

Overall, given the lack of prospective data available, it is clear that large randomized controlled trials will be needed to better clarify the utility of induction therapy, the risks associated with induction, and the optimal agent to be used for induction.

Maintenance

Maintenance immunosuppression is lifelong therapy after lung transplantation that is used to prevent acute and chronic rejection. There is additional focus on preventing side effects, which can include nephrotoxicity, cytopenias, infection and malignancy. Typically, maintenance immunosuppression regimens consist of a CNI, antiproliferative agent, and corticosteroids (Table 4). Previously, cyclosporine and azathioprine were used along with prednisone, however, the use of these two agents has decreased over the last several years. According to 2019 ISHLT registry data, the most commonly used maintenance regimen was tacrolimus, mycophenolate mofetil/mycophenolic acid (MMF/MPA), and prednisone (1). Mammalian target of rapamycin (mTOR) inhibitors have also emerged, and have been used as adjunctive agents for maintenance immunosuppression.

CNIs

CNIs have served as the backbone for conventional immunosuppression in solid organ transplant for over 25 years. The primary agents available are cyclosporine and tacrolimus. Cyclosporine is a lipophilic peptide that binds to cytoplasmic proteins called cyclophilins, while tacrolimus is a macrolide antibiotic that binds intracellular FK-binding proteins. In both cases, the drug-receptor complex that is formed in T-lymphocytes subsequently binds and inhibits calcineurin, a phosphatase needed to activate transcription factors for cytokines such as IL-2 and TNF-alpha. By inhibiting this cytokine production, cyclosporine and tacrolimus decrease activation and proliferation of T-lymphocytes (40-42).

Cyclosporine is available in intravenous formulation and two oral formulations, non-modified (Sandimmune^©) and modified (Neoral^©) (41,42). Absorption of non-modified cyclosporine is dependent on bile, so can exhibit variable gastrointestinal absorption patterns and therefore bioavailability. Modified cyclosporine is a microemulsion formula that does not depend upon bile salts for absorption and therefore exhibits more consistent absorption and increased bioavailability. Both oral formulations can be used but should not be considered to be interchangeable (43). Dosing of cyclosporine varies between centers but is typically done using trough or 2-hour post-dose drug levels. Generally, target trough levels range from 100–450 ng/mL, while target 2-hour post-dose levels range from 800–1,400 ng/mL. Target levels may be influenced by time from transplantation, with centers often targeting higher levels in the first 12 months after transplantation. The major side effects of cyclosporine include neurotoxicity (tremor, headache, neuropathy, seizures), hypertension, hyperlipidemia, nephrotoxicity (acute and chronic), electrolyte derangements (hyperkalemia, hypomagnesemia), diabetes, and hirsutism. Rare but serious side effects include posterior reversible encephalopathy syndrome (PRES) and thrombotic microangiopathies (41,42).

Tacrolimus is 10–100 times more potent than cyclosporine, and is available in intravenous and oral formulations (40). Tacrolimus is not currently available as an oral suspension, however, sublingual administration can be utilized at reduced doses. Extended release formulations of tacrolimus also exist, and are currently approved for immunosuppression following kidney transplantation (44). There is limited data for use of extended release tacrolimus in lung transplant patients, however, safety data has been promising, and there are several trials evaluating its efficacy compared to immediate release tacrolimus currently ongoing (45,46). Tacrolimus dosing is dosed based on drug level, with most centers targeting trough concentrations from 5–15 ng/mL. Many centers adjust target trough levels based on time from transplantation, with higher targets utilized during the first 12 months. Tacrolimus has similar adverse effects to cyclosporine, with some data suggesting increased rates of neurotoxicity and diabetes with tacrolimus (40).

Data evaluating tacrolimus and cyclosporine in the lung transplant population is limited to small prospective trials and retrospective studies (47-56). Overall, data suggests that tacrolimus is more efficacious than cyclosporine, with lower rates of acute and chronic rejection in several studies, though limited data suggesting differences in mortality when using these two agents. In a systematic review including 413 lung transplant patients from 3 prospective trials, Penninga et al. found that tacrolimus use was associated with lower rates of BOS, lymphocytic bronchitis and hypertension when compared to cyclosporine. There were no differences in survival, acute rejection, infection or malignancy (54). A meta-analysis of 297 patients from 3 randomized controlled trials by Fan et al. also showed no difference in mortality at 1 year, however, noted lower rates of acute rejection and a trend toward decreased BOS in patients treated with tacrolimus compared to cyclosporine (52). In an open label trial of 249 lung transplant recipients, Treede et al. found that tacrolimus use was associated with decreased incidence of BOS at 3 years when compared with cyclosporine, though rates of mortality and acute rejection were similar in both groups (53). Erdman et al. retrospectively analyzed 25,355 lung transplant recipients from the Scientific Registry of Transplant Recipients and found that a backbone immunosuppression regimen of tacrolimus and MMF resulted in a significantly lower risk of death or graft failure at 1 year compared to cyclosporine plus MMF and cyclosporine plus azathioprine (56). There is additional data supporting the use of tacrolimus over cyclosporine in other solid organ transplant recipients, with some studies demonstrating lower rates of 1 year mortality, graft loss and acute rejection with tacrolimus when compared to cyclosporine (57-61).

Due to the systemic toxicity associated with the use of enteral CNIs, there has been interest in the use of inhaled CNIs for prevention of acute and chronic rejection. In animal models of lung transplantation, inhaled tacrolimus has been shown to reduce histologic rejection and serum drug levels, though compelling human data has been limited to one case report (62-64). Inhaled cyclosporine has been more thoroughly evaluated in human subjects, and has shown some promise for treatment and prevention of CLAD (65-67). In a single-center, randomized, double-blind, placebo-controlled trial, Iacono et al. randomized 58 patients to inhaled cyclosporine plus usual care and placebo plus usual care (65). Though rates of acute rejection were similar in the two groups, survival at 3 years was improved in the cyclosporine group (3/28 patients died in the cyclosporine group vs. 14/30 in the control group, P=0.005). The inhaled cyclosporine group also demonstrated improved chronic rejection-free survival based on spirometric and histologic evaluation. There is no current FDA approved formulation of inhaled cyclosporine, and further studies will be needed to confirm its safety and efficacy.

Antiproliferative agents

The primary antiproliferative agents available for use in lung transplantation include azathioprine and MMF/MPA. Azathioprine is metabolized to 6-mercaptopurine (6-MP), which is further metabolized intracellularly to produce compounds that interfere with the production of adenine and guanine ribonucleotides. Reduced purine synthesis results in a decrease in production of circulating B- and T-lymphocytes, reduced immunoglobulin synthesis and decreased IL-2 secretion (68). MMF and mycophenolate sodium (MPS) are metabolized into MPA, a reversible inhibitor of the enzyme inosine monophosphate dehydrogenase, which is required for the de novo synthesis of guanosine nucleotides. By decreasing purine synthesis, MMF/MPA decreases B- and T-lymphocyte proliferation and antibody production (69-71). MMF/MPA may also contribute to immunosuppression via induction of apoptosis in activated T-lymphocytes, and by suppression of adhesion molecules that aid in lymphocyte recruitment.

Azathioprine is available in intravenous and oral formulations, and target dosing is typically 2 mg/kg daily (50–150 mg/day) (68). Major side effects include significant leukopenia, anemia, thrombocytopenia, hepatotoxicity, and pancreatitis. Azathioprine must be used with caution when used along with xanthine oxidase (XO) inhibitors, most notably allopurinol. XO is responsible in part for the metabolism of 6-MP to inactive metabolites, so XO inhibitors can potentiate the activity of azathioprine and 6-MP, resulting in an increased risk of significant bone marrow suppression. 6-MP is also metabolized by the enzyme thiopurine-S-methyltransferase (TPMT), which may exhibit decreased or absent activity in certain patients with genetic polymorphisms of the TPMT gene. These patients are also at risk for significant bone marrow suppression or additional side effects with typical doses of azathioprine.

Mycophenolate is the most commonly used antiproliferative agent in lung transplantation and is available in intravenous and two different oral formulations. MMF (CellCept^©) is available in intravenous and oral formulations, with target dosing of 1–1.5 g twice daily (69). MPS (Myfortic^©) is only available in oral formulation, with target dosing of 720 mg twice daily (70). Doses of MMF and MPS are not interchangeable, and require adjustment when switching between formulations. Common side effects of mycophenolate include leukopenia, anemia, thrombocytopenia, and gastrointestinal symptoms, most notably abdominal pain, nausea and diarrhea.

Data on the use of antiproliferative agents in lung transplantation is limited to retrospective studies and small prospective trials (72-77). This data has been largely mixed, however, there is some suggestion of improved outcomes and tolerability profile with mycophenolate compared to azathioprine. In a prospective cohort study of 156 lung transplant recipients, Speich et al. found that compared to azathioprine, the use of MMF was associated with decreased incidence, severity, and recurrence of acute rejection, in addition to reduced graft loss due to BOS (76). In a prospective, open-label, randomized controlled trial of 320 patients, McNeil et al. found no differences in the incidence of acute rejection, BOS, and survival in patients treated with MMF or azathioprine (75). However, more patients discontinued azathioprine than MMF (59.6% vs. 46.5%, P=0.02), with most patients withdrawing from the azathioprine group due to a lack of therapeutic response. Earlier data also suggests that MMF may be beneficial in stabilization and lung function and prevention of BOS progression (72).

mTOR inhibitors

Due to the systemic toxicities of CNIs, most notably renal dysfunction, interest in the use of mTOR inhibitors as adjunctive immunosuppressive agents has risen over the last several years. Sirolimus and everolimus bind to the FK binding protein, forming a complex that modulates mTOR, a kinase that participates in IL-2 mediated signal transduction and lymphocyte activation. Through the inhibition of mTOR, the cell cycle is arrested in the G1-S phase, thereby blocking cell cycle progression and proliferation in lymphocytes (78,79). mTOR inhibitors are available in oral tablets and oral solutions, and notable side effects include leukopenia, anemia, thrombocytopenia, dyslipidemia, hyperglycemia, impaired wound healing, pneumonitis, and venous thromboembolism.

Sirolimus and everolimus have been evaluated in the lung transplant population with primarily retrospective reviews and small prospective studies. Some data suggests that mTOR inhibitors may be added to backbone immunosuppression in order to reduce CNI doses and therefore preserve renal function (80-83). In a prospective, open-label, randomized controlled trial, Gottlieb et al. randomized 130 patients to conventional immunosuppression with CNI, antiproliferative agent, and steroids and an everolimus-based quadruple low CNI regimen, with lower target tacrolimus and cyclosporine troughs. The low CNI regimen demonstrated better eGFR at 12 months compared to conventional therapy, and there were no differences between the two groups in acute rejection, CLAD, or death (83). A retrospective review of 12 randomized controlled trials evaluating the use of sirolimus and everolimus to minimize tacrolimus dosage in solid organ transplants found that including an mTOR inhibitor plus tacrolimus minimization better preserves renal function with no changes in patient survival or graft rejection rates (84). A current prospective, randomized trial is evaluating the use of alemtuzumab induction followed by low-dose everolimus and low-dose tacrolimus compared to traditional immunosuppression with typical doses of tacrolimus (24).

mTOR inhibitors are potent inhibitors of fibroblast proliferation, so there has also been interest in the use of these agents for the treatment and prevention of CLAD in lung transplant recipients. While some small studies have suggested potential benefit to mTOR inhibitors in preserving post-transplant lung function, larger studies and prospective trials have largely failed to show consistent benefit (85-94). In a randomized, double-blind clinical trial, Snell et al. randomized 213 BOS-free patients to everolimus or azathioprine in combination with cyclosporine and steroids, and found that change in FEV1 >15%, change in FEV1 >15% with BOS, and acute rejection were less common in everolimus group at 12 months (89). However, at 24 months, only incidence of acute rejection remained significantly lower in the everolimus group. An open label trial of 180 patients comparing use of sirolimus to azathioprine found no differences in acute rejection, chronic rejection, and graft failure at one year, with a higher rate of adverse events leading to discontinuation of sirolimus compared to azathioprine (90).

One of the major concerns regarding the widespread use of mTOR inhibitors is the development of severe, and sometimes catastrophic side effects with these agents. The use of sirolimus in the immediate post-operative period has been associated with severe wound healing complications, notably anastomotic airway dehiscence. In a prospective study of 15 lung transplant recipients receiving an immunosuppressive regimen with sirolimus, tacrolimus and prednisone, 4 patients developed significant airway complications, 3 of whom died. Similarly, in a pilot study evaluating a sirolimus-based immunosuppression regimen, 3/4 patients developed severe wound healing complications, including 2 patients developing bronchial airway dehiscence, resulting in 1 death (95,96). Consequently, the use of mTOR inhibitors has largely been limited to 3 months after initial transplantation. Sirolimus and everolimus have been associated with additional adverse reactions, notably interstitial pneumonitis and lung disease, and venous thromboembolism (97-99). Further data will be needed to clarify the safety of mTOR inhibitors, and to better delineate their role in lung transplant immunosuppression.

Belatacept

Belatacept is a costimulatory antagonist that serves to prevent binding of CD28 on T-cells, and thereby limit T-cell activation and replication in response to antigen presenting cells (100). Belatacept has been shown to be associated with improved renal function, reduced incidence of de novo donor specific antibodies (DSA), and favorable impacts on graft survival when compared to CNIs in patients undergoing kidney transplantation. Experience with belatacept in lung transplant has been limited, with prior data limited to small, retrospective case series (101-104). However, in a recent pilot randomized controlled trial, Huang et al. randomized 27 patients to de novo immunosuppression with belatacept or traditional immunosuppression with tacrolimus, MMF, and prednisone. The trial was stopped early after 3 patients in the belatacept group died, compared to none in the control group. Following cessation of randomization, there were 2 additional deaths in belatacept group, yielding a total of 5 deaths in the belatacept group and none in the control group (P=0.016) (105). Additionally, there have been case reports of severe, fulminant ACR in patients who underwent transition to belatacept from CNI-based immunosuppression (106,107). In light of these results, belatacept does not currently have a role in maintenance immunosuppression for lung transplant patients.

Corticosteroids

Corticosteroids have been used in both induction and maintenance immunosuppression throughout the history of solid organ transplants. Corticosteroids affect the immune system in myriad ways, but primarily lead to immunosuppression through sequestration of T-lymphocytes in the reticuloendothelial system, prevention of T-cell proliferation, inhibition of inflammatory cytokine production, and alteration of lymphocyte recruitment and migration (108-110). The most commonly used agents in lung transplantation are prednisone and methylprednisolone. Dosing of corticosteroids varies by center, but generally, initial doses range from 500–1,000 mg daily in the immediate perioperative period, with a subsequent taper over weeks to a target maintenance dose of 2.5–5 mg daily. The side effects of corticosteroids are well known, and include hypertension, hyperlipidemia, weight gain, hyperglycemia and diabetes mellitus, osteopenia and increased fracture risk, poor wound healing, neuropsychiatric changes, and increased risk of infection. In light of the long-term sequelae of chronic steroid therapy, there has been some interest in steroid withdrawal in the lung transplant population. There is some data suggesting that in carefully selected patients with stable lung function, steroids may be successfully withdrawn, with subsequent improvement in cholesterol profiles, blood pressure control, and hyperglycemia (111,112). However, these data are collected from small, observational studies, so further research will be required to determine if steroid withdrawal in lung transplantation can be more broadly applied. Corticosteroids are also a first line treatment for ACR. Initial episodes of ACR are typically treated with a short course of high-dose methylprednisolone (10–15 mg/kg daily for 3 days), followed by a taper of prednisone to the maintenance dose. There are no studies evaluating alternative steroid dosing strategies or treatment paradigms in the lung transplant population.

The role of inhaled corticosteroids in the lung transplantation population remains unclear. Inhaled steroids may lead to improvements in symptoms and FEV1 in patients who develop BOS following allogeneic stem cell transplantation (113-115). However, data for the use of steroids in the treatment of either acute or chronic rejection in lung transplantation is largely limited to small case series (116,117). In a randomized controlled trial of 30 lung transplant patients, Whitford et al. evaluated the use of inhaled fluticasone vs. placebo added to routine maintenance immunosuppression, and found no differences in rates of treated acute rejection, development of stage 1 BOS, incidence of fungal infection or survival at 3 months and 2 years (118).

Adjunctive therapies

Given the limitations of conventional immunosuppression, there is considerable interest in the development of additional therapies for the treatment and prevention of both ACR and CLAD. Research has demonstrated the potential utility of numerous agents, including azithromycin, montelukast, statins, and pirfenidone (Table 5).

Azithromycin is a macrolide antibiotic with anti-inflammatory properties that has been utilized in the lung transplantation population primarily for its potential benefit in stabilization of lung function and prevention of CLAD. Data evaluating azithromycin consists of retrospective studies and small prospective trials. Overall, this data suggests that azithromycin may contribute to stabilization of lung function and improvement in FEV1, with some studies demonstrating a reduction in the incidence of CLAD (119-132). In a randomized, double-blind, placebo-controlled trial, Vos et al. randomized 83 patients to azithromycin or placebo and found that those treated with azithromycin had lower rates of BOS (12.5% vs. 44.2%, P=0.0017), improved FEV1, and lower airway neutrophilia. Overall survival, acute rejection, pneumonitis, and colonization were similar between the intervention and control groups (127). There is also some data supporting the use of azithromycin to prevent progression of CLAD. In a meta-analysis of 10 studies, including 140 patients with known BOS, treatment with azithromycin was associated with an increase in FEV1 and a lower likelihood of death from BOS.

Montelukast is a leukotriene receptor antagonist that has been evaluated as a potential adjunct therapy for patients with known CLAD. Data is limited, however, one retrospective study demonstrated attenuation in the decline of FEV1 in patients with BOS treated with montelukast (133). However, randomized trial data has shown no difference in rates of lung function decline, graft loss, or rejection in patients treated with montelukast compared to placebo (134).

Statins are hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, and are used broadly as lipid lowering therapy and for cardiovascular disease. Statins are widely accepted to exhibit anti-inflammatory properties, and are thought to play a significant role in reducing inflammation associated with atherogenesis (135). In the field of lung transplantation, statins have been shown to prevent the development of BOS in rats (136). In retrospective studies, statin use has also been associated with lower rates of acute rejection, improved graft function, slower onset of BOS, and improved survival (137,138). Though widely used for other indications, further study is needed to clarify the role of statins in the lung transplantation population.

Pirfenidone is an antifibrotic agent that downregulates the production of growth factors and procollagens. It has been used in pulmonary fibrosis, and has been shown to reduce disease progression and decline in lung function in patients with that disease (139). Pirfenidone has been shown to decrease graft obliteration in animal models of BOS, so interest has arisen in its use for fibroproliferative BOS (140). However, data for the use of pirfenidone in human subjects is largely limited to case reports and small cohort studies (141,142). A recent multicenter, randomized, double-blind placebo controlled trial in patients with BOS did not show a significant benefit of pirfenidone on pulmonary function decline, though complete data from this trial is not currently available (143,144). There is a small trial ongoing evaluating the use of pirfenidone in RAS, the restrictive variant of CLAD (NCT03359863), and a large trial evaluating the use of nintedanib, another antifibrotic agent, in patients with BOS (NCT03283007).

Rejection

An in-depth discussion of ACR, antibody mediated rejection (AMR), and CLAD is beyond the scope of this review. However, many of the agents used for induction and maintenance immunosuppression can be used in the treatment of different forms of rejection. Regarding ACR, as above, first line treatment at most centers is high dose corticosteroids. For persistent or recurrent ACR, other options include ATG, which has not been studied in lung transplant patients, and alemtuzumab, which has shown some promise in small case series (145). Additional management strategies include adjusting maintenance immunosuppression, adding an mTOR inhibitor to backbone immunosuppression, and the use of extracorporeal photopheresis (ECP), and total lymphoid irradiation (TLI) (146-150). AMR is challenging to treat, and there is limited data supporting therapeutic options. Therapies used generally focus on antibody reduction, and include plasmapheresis, intravenous immunoglobulin (IVIG), rituximab, proteasome inhibitors, and complement inhibitors (151-167). CLAD is also challenging to treat (168). As above, azithromycin and montelukast may help stabilize lung function, and pirfenidone is currently being evaluated for both BOS and restrictive CLAD (96-111). Alemtuzumab has been used for CLAD, with retrospective data demonstrating promise for stabilization of lung function, and ATG has been shown to demonstrate improved lung function in 40% of patients in one retrospective review, albeit with a high rate of serious adverse effects, including serum sickness, cytokine release syndrome, and infection (145,169-171). ECP, TLI and re-transplantation can also be considered for these patients (169,172-180).

Conclusions

Lung transplantation continues to rise in prominence as a treatment for patients with advanced lung disease. However, long-term survival and transplant success continue to be limited by acute rejection, CLAD, infection, and the deleterious side effects associated with immunosuppression. Current strategies for induction and maintenance immunosuppression, along with treatment paradigms for acute rejection and CLAD have evolved over the last several decades. Still, randomized clinical trials are needed in order to identify the optimal strategies for immune suppression following transplant. Furthermore, additional research is needed to identify additional options for immune suppressive agents, along with adjunctive therapies that may help address the drivers of morbidity and mortality in the lung transplant population.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (George Makdisi) for the series “Lung Transplant: Current Status and Challenges” published in Current Challenges in Thoracic Surgery. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://ccts.amegroups.com/article/view/10.21037/ccts-21-42/rc

Peer Review File: Available at https://ccts.amegroups.com/article/view/10.21037/ccts-21-42/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://ccts.amegroups.com/article/view/10.21037/ccts-21-42/coif). The series “Lung Transplant: Current Status and Challenges” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Chambers DC, Cherikh WS, Harhay MO, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-sixth adult lung and heart-lung transplantation Report-2019; Focus theme: Donor and recipient size match. J Heart Lung Transplant 2019;38:1042-55. [Crossref] [PubMed]
2. Chambers DC, Zuckermann A, Cherikh WS, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: 37th adult lung transplantation report - 2020; focus on deceased donor characteristics. J Heart Lung Transplant 2020;39:1016-27. [Crossref] [PubMed]
3. Chambers DC, Perch M, Zuckermann A, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-eighth adult lung transplantation report - 2021; Focus on recipient characteristics. J Heart Lung Transplant 2021;40:1060-72. [Crossref] [PubMed]
4. Glanville AR, Verleden GM, Todd JL, et al. Chronic lung allograft dysfunction: Definition and update of restrictive allograft syndrome-A consensus report from the Pulmonary Council of the ISHLT. J Heart Lung Transplant 2019;38:483-92. [Crossref] [PubMed]
5. Simulect [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation, 2003.
6. Zenapax [package insert]. Nutley, NJ: Roche Pharmaceuticals, 2003.
7. Thymoglobulin [package insert]. Laval, Quebec: Sanofi, 2016
8. Thymoglobulin [package insert]. Cambridge, MA: Genzyme, 2017.
9. Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia 2007;21:1387-94. [Crossref] [PubMed]
10. Campath [package insert]. Cambridge, MA: Millennium and ILEX Partners, 2003.
11. Morris PJ, Russell NK. Alemtuzumab (Campath-1H): a systematic review in organ transplantation. Transplantation 2006;81:1361-7. [Crossref] [PubMed]
12. Ruck T, Bittner S, Wiendl H, et al. Alemtuzumab in Multiple Sclerosis: Mechanism of Action and Beyond. Int J Mol Sci 2015;16:16414-39. [Crossref] [PubMed]
13. Palmer SM, Miralles AP, Lawrence CM, et al. Rabbit antithymocyte globulin decreases acute rejection after lung transplantation: results of a randomized, prospective study. Chest 1999;116:127-33. [Crossref] [PubMed]
14. Garrity ER Jr, Villanueva J, Bhorade SM, et al. Low rate of acute lung allograft rejection after the use of daclizumab, an interleukin 2 receptor antibody. Transplantation 2001;71:773-7. [Crossref] [PubMed]
15. Borro JM, De la Torre M, Míguelez C, et al. Comparative study of basiliximab treatment in lung transplantation. Transplant Proc 2005;37:3996-8. [Crossref] [PubMed]
16. Hachem RR, Edwards LB, Yusen RD, et al. The impact of induction on survival after lung transplantation: an analysis of the International Society for Heart and Lung Transplantation Registry. Clin Transplant 2008;22:603-8. [Crossref] [PubMed]
17. Cai J, Terasaki PI. Induction immunosuppression improves long-term graft and patient outcome in organ transplantation: an analysis of United Network for Organ Sharing registry data. Transplantation 2010;90:1511-5. [Crossref] [PubMed]
18. Jaksch P, Wiedemann D, Augustin V, et al. Antithymocyte globulin induction therapy improves survival in lung transplantation for cystic fibrosis. Transpl Int 2013;26:34-41. [Crossref] [PubMed]
19. Furuya Y, Jayarajan SN, Taghavi S, et al. The Impact of Alemtuzumab and Basiliximab Induction on Patient Survival and Time to Bronchiolitis Obliterans Syndrome in Double Lung Transplantation Recipients. Am J Transplant 2016;16:2334-41. [Crossref] [PubMed]
20. Whitson BA, Lehman A, Wehr A, et al. To induce or not to induce: a 21st century evaluation of lung transplant immunosuppression's effect on survival. Clin Transplant 2014;28:450-61. [Crossref] [PubMed]
21. Kirkby S, Whitson BA, Wehr AM, et al. Survival benefit of induction immunosuppression in cystic fibrosis lung transplant recipients. J Cyst Fibros 2015;14:104-10. [Crossref] [PubMed]
22. Duffy JS Jr, Tumin D, Pope-Harman A, et al. Induction Therapy for Lung Transplantation in COPD: Analysis of the UNOS Registry. COPD 2016;13:647-52. [Crossref] [PubMed]
23. Benazzo A, Schwarz S, Muckenhuber M, et al. Alemtuzumab induction combined with reduced maintenance immunosuppression is associated with improved outcomes after lung transplantation: A single centre experience. PLoS One 2019;14:e0210443. [Crossref] [PubMed]
24. Benazzo A, Auner S, Boehm PM, et al. Outcomes with alemtuzumab induction therapy in lung transplantation: a comprehensive large-scale single-center analysis. Transpl Int 2021;34:2633-43. [Crossref] [PubMed]
25. Brock MV, Borja MC, Ferber L, et al. Induction therapy in lung transplantation: a prospective, controlled clinical trial comparing OKT3, anti-thymocyte globulin, and daclizumab. J Heart Lung Transplant 2001;20:1282-90. [Crossref] [PubMed]
26. Hartwig MG, Snyder LD, Appel JZ 3rd, et al. Rabbit anti-thymocyte globulin induction therapy does not prolong survival after lung transplantation. J Heart Lung Transplant 2008;27:547-53. [Crossref] [PubMed]
27. van Loenhout KC, Groves SC, Galazka M, et al. Early outcomes using alemtuzumab induction in lung transplantation. Interact Cardiovasc Thorac Surg 2010;10:190-4. [Crossref] [PubMed]
28. Penninga L, Møller CH, Penninga EI, et al. Antibody induction therapy for lung transplant recipients. Cochrane Database Syst Rev 2013;CD008927. [Crossref] [PubMed]
29. Snell GI, Westall GP, Levvey BJ, et al. A randomized, double-blind, placebo-controlled, multicenter study of rabbit ATG in the prophylaxis of acute rejection in lung transplantation. Am J Transplant 2014;14:1191-8. [Crossref] [PubMed]
30. Shyu S, Dew MA, Pilewski JM, et al. Five-year outcomes with alemtuzumab induction after lung transplantation. J Heart Lung Transplant 2011;30:743-54. [Crossref] [PubMed]
31. Ailawadi G, Smith PW, Oka T, et al. Effects of induction immunosuppression regimen on acute rejection, bronchiolitis obliterans, and survival after lung transplantation. J Thorac Cardiovasc Surg 2008;135:594-602. [Crossref] [PubMed]
32. Clinckart F, Bulpa P, Jamart J, et al. Basiliximab as an alternative to antithymocyte globulin for early immunosuppression in lung transplantation. Transplant Proc 2009;41:607-9. [Crossref] [PubMed]
33. Mullen JC, Oreopoulos A, Lien DC, et al. A randomized, controlled trial of daclizumab vs anti-thymocyte globulin induction for lung transplantation. J Heart Lung Transplant 2007;26:504-10. [Crossref] [PubMed]
34. Hachem RR, Chakinala MM, Yusen RD, et al. A comparison of basiliximab and anti-thymocyte globulin as induction agents after lung transplantation. J Heart Lung Transplant 2005;24:1320-6. [Crossref] [PubMed]
35. McCurry KR, Iacono A, Zeevi A, et al. Early outcomes in human lung transplantation with Thymoglobulin or Campath-1H for recipient pretreatment followed by posttransplant tacrolimus near-monotherapy. J Thorac Cardiovasc Surg 2005;130:528-37. [Crossref] [PubMed]
36. Jaksch P, Ankersmit J, Scheed A, et al. Alemtuzumab in lung transplantation: an open-label, randomized, prospective single center study. Am J Transplant 2014;14:1839-45. [Crossref] [PubMed]
37. Whited LK, Latran MJ, Hashmi ZA, et al. Evaluation of Alemtuzumab Versus Basiliximab Induction: A Retrospective Cohort Study in Lung Transplant Recipients. Transplantation 2015;99:2190-5. [Crossref] [PubMed]
38. Furukawa M, Chan EG, Ryan JP, et al. Induction Strategies in Lung Transplantation: Alemtuzumab vs. Basiliximab a Single-Center Experience. Front Immunol 2022;13:864545. [Crossref] [PubMed]
39. Li KHC, Ho JCS, Recaldin B, et al. Acute Cellular Rejection and Infection Rates in Alemtuzumab vs Traditional Induction Therapy Agents for Lung and Heart Transplantation: A Systematic Review and Meta-analysis. Transplant Proc 2018;50:3723-31. [Crossref] [PubMed]
40. Prograf [package insert]. Deerfield, IL: Astellas Pharma, 2012.
41. Neoral [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation, 2009.
42. Sandimmune [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation, 2006.
43. Kahan BD, Dunn J, Fitts C, et al. Reduced inter- and intrasubject variability in cyclosporine pharmacokinetics in renal transplant recipients treated with a microemulsion formulation in conjunction with fasting, low-fat meals, or high-fat meals. Transplantation 1995;59:505-11. [Crossref] [PubMed]
44. Envarsus [package insert]. Cary, NC: Veloxis Pharmaceuticals, 2018.
45. Méndez A, Berastegui C, López-Meseguer M, et al. Pharmacokinetic study of conversion from tacrolimus twice-daily to tacrolimus once-daily in stable lung transplantation. Transplantation 2014;97:358-62. [Crossref] [PubMed]
46. Sintes H, Sáez-Giménez B, Berastegui C, et al. Pharmacokinetic Study of Conversion Between 2 Formulations of Once-daily Extended-release Tacrolimus in Stable Lung Transplant Patients. Transplantation 2018;102:e439-46. [Crossref] [PubMed]
47. Griffith BP, Bando K, Hardesty RL, et al. A prospective randomized trial of FK506 versus cyclosporine after human pulmonary transplantation. Transplantation 1994;57:848-51. [Crossref] [PubMed]
48. Keenan RJ, Konishi H, Kawai A, et al. Clinical trial of tacrolimus versus cyclosporine in lung transplantation. Ann Thorac Surg 1995;60:580-4; discussion 584-5. [Crossref] [PubMed]
49. Treede H, Klepetko W, Reichenspurner H, et al. Tacrolimus versus cyclosporine after lung transplantation: a prospective, open, randomized two-center trial comparing two different immunosuppressive protocols. J Heart Lung Transplant 2001;20:511-7. [Crossref] [PubMed]
50. Zuckermann A, Reichenspurner H, Birsan T, et al. Cyclosporine A versus tacrolimus in combination with mycophenolate mofetil and steroids as primary immunosuppression after lung transplantation: one-year results of a 2-center prospective randomized trial. J Thorac Cardiovasc Surg 2003;125:891-900. [Crossref] [PubMed]
51. Hachem RR, Yusen RD, Chakinala MM, et al. A randomized controlled trial of tacrolimus versus cyclosporine after lung transplantation. J Heart Lung Transplant 2007;26:1012-8. [Crossref] [PubMed]
52. Fan Y, Xiao YB, Weng YG. Tacrolimus versus cyclosporine for adult lung transplant recipients: a meta-analysis. Transplant Proc 2009;41:1821-4. [Crossref] [PubMed]
53. Treede H, Glanville AR, Klepetko W, et al. Tacrolimus and cyclosporine have differential effects on the risk of development of bronchiolitis obliterans syndrome: results of a prospective, randomized international trial in lung transplantation. J Heart Lung Transplant 2012;31:797-804. [Crossref] [PubMed]
54. Penninga L, Penninga EI, Møller CH, et al. Tacrolimus versus cyclosporin as primary immunosuppression for lung transplant recipients. Cochrane Database Syst Rev 2013;CD008817. [Crossref] [PubMed]
55. Celik MR, Lederer DJ, Wilt J, et al. Tacrolimus and azathioprine versus cyclosporine and mycophenolate mofetil after lung transplantation: a retrospective cohort study. J Heart Lung Transplant 2009;28:697-703. [Crossref] [PubMed]
56. Erdman J, Wolfram J, Nimke D, et al. Lung Transplant Outcomes in Adults in the United States: Retrospective Cohort Study Using Real-world Evidence from the SRTR. Transplantation 2022;106:1233-42. [Crossref] [PubMed]
57. Vincenti F, Friman S, Scheuermann E, et al. Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus. Am J Transplant 2007;7:1506-14. [Crossref] [PubMed]
58. Flechner SM, Kobashigawa J, Klintmalm G. Calcineurin inhibitor-sparing regimens in solid organ transplantation: focus on improving renal function and nephrotoxicity. Clin Transplant 2008;22:1-15. [PubMed]
59. McAlister VC, Haddad E, Renouf E, et al. Cyclosporin versus tacrolimus as primary immunosuppressant after liver transplantation: a meta-analysis. Am J Transplant 2006;6:1578-85. [Crossref] [PubMed]
60. Neurohr C, Huppmann P, Zimmermann G, et al. Tacrolimus and mycophenolate mofetil as first line immunosuppression after lung transplantation. Transpl Int 2009;22:635-43. [Crossref] [PubMed]
61. Penninga L, Møller CH, Gustafsson F, et al. Tacrolimus versus cyclosporine as primary immunosuppression after heart transplantation: systematic review with meta-analyses and trial sequential analyses of randomised trials. Eur J Clin Pharmacol 2010;66:1177-87. [Crossref] [PubMed]
62. Ide N, Nagayasu T, Matsumoto K, et al. Efficacy and safety of inhaled tacrolimus in rat lung transplantation. J Thorac Cardiovasc Surg 2007;133:548-53. [Crossref] [PubMed]
63. Das NA, Peters JI, Simmons JD, et al. The efficacy of inhaled nanoparticle tacrolimus in preventing rejection in an orthotopic rat lung transplant model. J Thorac Cardiovasc Surg 2017;154:2144-2151.e1. [Crossref] [PubMed]
64. Hayes D Jr, Zwischenberger JB, Mansour HM. Aerosolized tacrolimus: a case report in a lung transplant recipient. Transplant Proc 2010;42:3876-9. [Crossref] [PubMed]
65. Iacono AT, Johnson BA, Grgurich WF, et al. A randomized trial of inhaled cyclosporine in lung-transplant recipients. N Engl J Med 2006;354:141-50. [Crossref] [PubMed]
66. Iacono A, Wijesinha M, Rajagopal K, et al. A randomised single-centre trial of inhaled liposomal cyclosporine for bronchiolitis obliterans syndrome post-lung transplantation. ERJ Open Res 2019;5:e00167-2019. [Crossref] [PubMed]
67. Neurohr C, Kneidinger N, Ghiani A, et al. A randomized controlled trial of liposomal cyclosporine A for inhalation in the prevention of bronchiolitis obliterans syndrome following lung transplantation. Am J Transplant 2022;22:222-9. [Crossref] [PubMed]
68. Imuran [package insert]. San Diego, CA: Prometheus Laboratories Inc., 2011.
69. CellCept [package insert]. Nutley, NJ: Roche Laboratories Inc., 1998.
70. Myfortic [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation, 2013.
71. Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 2000;47:85-118. [Crossref] [PubMed]
72. Whyte RI, Rossi SJ, Mulligan MS, et al. Mycophenolate mofetil for obliterative bronchiolitis syndrome after lung transplantation. Ann Thorac Surg 1997;64:945-8. [Crossref] [PubMed]
73. Zuckermann A, Klepetko W, Birsan T, et al. Comparison between mycophenolate mofetil- and azathioprine-based immunosuppressions in clinical lung transplantation. J Heart Lung Transplant 1999;18:432-40. [Crossref] [PubMed]
74. Palmer SM, Baz MA, Sanders L, et al. Results of a randomized, prospective, multicenter trial of mycophenolate mofetil versus azathioprine in the prevention of acute lung allograft rejection. Transplantation 2001;71:1772-6. [Crossref] [PubMed]
75. McNeil K, Glanville AR, Wahlers T, et al. Comparison of mycophenolate mofetil and azathioprine for prevention of bronchiolitis obliterans syndrome in de novo lung transplant recipients. Transplantation 2006;81:998-1003. [Crossref] [PubMed]
76. Speich R, Schneider S, Hofer M, et al. Mycophenolate mofetil reduces alveolar inflammation, acute rejection and graft loss due to bronchiolitis obliterans syndrome after lung transplantation. Pulm Pharmacol Ther 2010;23:445-9. [Crossref] [PubMed]
77. Vos M, Plasmeijer EI, van Bemmel BC, et al. Azathioprine to mycophenolate mofetil transition and risk of squamous cell carcinoma after lung transplantation. J Heart Lung Transplant 2018;37:853-9. [Crossref] [PubMed]
78. Rapamune [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc., 2015.
79. Afinitor [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corportation, 2010.
80. Shitrit D, Rahamimov R, Gidon S, et al. Use of sirolimus and low-dose calcineurin inhibitor in lung transplant recipients with renal impairment: results of a controlled pilot study. Kidney Int 2005;67:1471-5. [Crossref] [PubMed]
81. Roman A, Ussetti P, Zurbano F, et al. A retrospective 12-month study of conversion to everolimus in lung transplant recipients. Transplant Proc 2011;43:2693-8. [Crossref] [PubMed]
82. Gullestad L, Eiskjaer H, Gustafsson F, et al. Long-term outcomes of thoracic transplant recipients following conversion to everolimus with reduced calcineurin inhibitor in a multicenter, open-label, randomized trial. Transpl Int 2016;29:819-29. [Crossref] [PubMed]
83. Gottlieb J, Neurohr C, Müller-Quernheim J, et al. A randomized trial of everolimus-based quadruple therapy vs standard triple therapy early after lung transplantation. Am J Transplant 2019;19:1759-69. [Crossref] [PubMed]
84. Peddi VR, Wiseman A, Chavin K, et al. Review of combination therapy with mTOR inhibitors and tacrolimus minimization after transplantation. Transplant Rev (Orlando) 2013;27:97-107. [Crossref] [PubMed]
85. Cahill BC, Somerville KT, Crompton JA, et al. Early experience with sirolimus in lung transplant recipients with chronic allograft rejection. J Heart Lung Transplant 2003;22:169-76. [Crossref] [PubMed]
86. Azzola A, Havryk A, Chhajed P, et al. Everolimus and mycophenolate mofetil are potent inhibitors of fibroblast proliferation after lung transplantation. Transplantation 2004;77:275-80. [Crossref] [PubMed]
87. Hernández RL, Gil PU, Gallo CG, et al. Rapamycin in lung transplantation. Transplant Proc 2005;37:3999-4000. [Crossref] [PubMed]
88. Villanueva J, Boukhamseen A, Bhorade SM. Successful use in lung transplantation of an immunosuppressive regimen aimed at reducing target blood levels of sirolimus and tacrolimus. J Heart Lung Transplant 2005;24:421-5. [Crossref] [PubMed]
89. Snell GI, Valentine VG, Vitulo P, et al. Everolimus versus azathioprine in maintenance lung transplant recipients: an international, randomized, double-blind clinical trial. Am J Transplant 2006;6:169-77. [Crossref] [PubMed]
90. Bhorade S, Ahya VN, Baz MA, et al. Comparison of sirolimus with azathioprine in a tacrolimus-based immunosuppressive regimen in lung transplantation. Am J Respir Crit Care Med 2011;183:379-87. [Crossref] [PubMed]
91. Parada MT, Alba A, Sepúlveda C, et al. Long-term use of everolimus in lung transplant patients. Transplant Proc 2011;43:2313-5. [Crossref] [PubMed]
92. Sacher VY, Fertel D, Srivastava K, et al. Effects of prophylactic use of sirolimus on bronchiolitis obliterans syndrome development in lung transplant recipients. Ann Thorac Surg 2014;97:268-74. [Crossref] [PubMed]
93. Glanville AR, Aboyoun C, Klepetko W, et al. Three-year results of an investigator-driven multicenter, international, randomized open-label de novo trial to prevent BOS after lung transplantation. J Heart Lung Transplant 2015;34:16-25. [Crossref] [PubMed]
94. de Souza AR, Dos Santos TAGM, Von Jakitsch CB, et al. Mammalian Target of Rapamycin Inhibitors Vs Calcineurin Inhibitors in Chronic Graft Rejection After Lung Transplantation: A Systematic Review and Meta-Analysis. Transplant Proc 2021;53:3056-64. [Crossref] [PubMed]
95. King-Biggs MB, Dunitz JM, Park SJ, et al. Airway anastomotic dehiscence associated with use of sirolimus immediately after lung transplantation. Transplantation 2003;75:1437-43. [Crossref] [PubMed]
96. Groetzner J, Kur F, Spelsberg F, et al. Airway anastomosis complications in de novo lung transplantation with sirolimus-based immunosuppression. J Heart Lung Transplant 2004;23:632-8. [Crossref] [PubMed]
97. Garrean S, Massad MG, Tshibaka M, et al. Sirolimus-associated interstitial pneumonitis in solid organ transplant recipients. Clin Transplant 2005;19:698-703. [Crossref] [PubMed]
98. Ahya VN, McShane PJ, Baz MA, et al. Increased risk of venous thromboembolism with a sirolimus-based immunosuppression regimen in lung transplantation. J Heart Lung Transplant 2011;30:175-81. [Crossref] [PubMed]
99. Lopez P, Kohler S, Dimri S. Interstitial Lung Disease Associated with mTOR Inhibitors in Solid Organ Transplant Recipients: Results from a Large Phase III Clinical Trial Program of Everolimus and Review of the Literature. J Transplant 2014;2014:305931. [Crossref] [PubMed]
100. Nulojix [package insert]. Princeton, NJ: Bristol-Myers Squibb Company, 2014.
101. Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant 2010;10:535-46. [Crossref] [PubMed]
102. Vincenti F, Larsen CP, Alberu J, et al. Three-year outcomes from BENEFIT, a randomized, active-controlled, parallel-group study in adult kidney transplant recipients. Am J Transplant 2012;12:210-7. [Crossref] [PubMed]
103. Timofte I, Terrin M, Barr E, et al. Belatacept for renal rescue in lung transplant patients. Transpl Int 2016;29:453-63. [Crossref] [PubMed]
104. Iasella CJ, Winstead RJ, Moore CA, et al. Maintenance Belatacept-Based Immunosuppression in Lung Transplantation Recipients Who Failed Calcineurin Inhibitors. Transplantation 2018;102:171-7. [Crossref] [PubMed]
105. Huang HJ, Schechtman K, Askar M, et al. A pilot randomized controlled trial of de novo belatacept-based immunosuppression following anti-thymocyte globulin induction in lung transplantation. Am J Transplant 2022;22:1884-92. [Crossref] [PubMed]
106. Brugière O, Cazes A, Champion L, et al. Fulminant Acute Respiratory Distress Syndrome After Calcineurin Inhibitor-belatacept Conversion in a Lung Transplant Recipient. Transplantation 2018;102:e255-6. [Crossref] [PubMed]
107. Nachiappan A, Fallah T, Willert R, et al. Severe Acute Cellular Rejection With High-Grade Lymphocytic Bronchiolitis Following Transition from Tacrolimus to Belatacept in a Lung Transplantation Recipient: A Case Report. Transplant Proc 2022;54:165-8. [Crossref] [PubMed]
108. Barshes NR, Goodpastor SE, Goss JA. Pharmacologic immunosuppression. Front Biosci 2004;9:411-20. [Crossref] [PubMed]
109. Barnes PJ. How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol 2006;148:245-54. [Crossref] [PubMed]
110. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. N Engl J Med 2005;353:1711-23. [Crossref] [PubMed]
111. Borro JM, Solé A, De la Torre M, et al. Steroid withdrawal in lung transplant recipients. Transplant Proc 2005;37:3991-3. [Crossref] [PubMed]
112. Shitrit D, Bendayan D, Sulkes J, et al. Successful steroid withdrawal in lung transplant recipients: result of a pilot study. Respir Med 2005;99:596-601. [Crossref] [PubMed]
113. Bergeron A, Belle A, Chevret S, et al. Combined inhaled steroids and bronchodilatators in obstructive airway disease after allogeneic stem cell transplantation. Bone Marrow Transplant 2007;39:547-53. [Crossref] [PubMed]
114. Bergeron A, Chevret S, Chagnon K, et al. Budesonide/Formoterol for bronchiolitis obliterans after hematopoietic stem cell transplantation. Am J Respir Crit Care Med 2015;191:1242-9. [Crossref] [PubMed]
115. Kim SW, Rhee CK, Kim YJ, et al. Therapeutic effect of budesonide/formoterol, montelukast and N-acetylcysteine for bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation. Respir Res 2016;17:63. [Crossref] [PubMed]
116. Speich R, Boehler A, Russi EW, et al. A case report of a double-blind, randomized trial of inhaled steroids in a patient with lung transplant bronchiolitis obliterans. Respiration 1997;64:375-80. [Crossref] [PubMed]
117. De Soyza A, Fisher AJ, Small T, et al. Inhaled corticosteroids and the treatment of lymphocytic bronchiolitis following lung transplantation. Am J Respir Crit Care Med 2001;164:1209-12. [Crossref] [PubMed]
118. Whitford H, Walters EH, Levvey B, et al. Addition of inhaled corticosteroids to systemic immunosuppression after lung transplantation: a double-blind, placebo-controlled trial. Transplantation 2002;73:1793-9. [Crossref] [PubMed]
119. Gerhardt SG, McDyer JF, Girgis RE, et al. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study. Am J Respir Crit Care Med 2003;168:121-5. [Crossref] [PubMed]
120. Verleden GM, Dupont LJ. Azithromycin therapy for patients with bronchiolitis obliterans syndrome after lung transplantation. Transplantation 2004;77:1465-7. [Crossref] [PubMed]
121. Shitrit D, Bendayan D, Gidon S, et al. Long-term azithromycin use for treatment of bronchiolitis obliterans syndrome in lung transplant recipients. J Heart Lung Transplant 2005;24:1440-3. [Crossref] [PubMed]
122. Yates B, Murphy DM, Forrest IA, et al. Azithromycin reverses airflow obstruction in established bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2005;172:772-5. [Crossref] [PubMed]
123. Verleden GM, Vanaudenaerde BM, Dupont LJ, et al. Azithromycin reduces airway neutrophilia and interleukin-8 in patients with bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2006;174:566-70. [Crossref] [PubMed]
124. Gottlieb J, Szangolies J, Koehnlein T, et al. Long-term azithromycin for bronchiolitis obliterans syndrome after lung transplantation. Transplantation 2008;85:36-41. [Crossref] [PubMed]
125. Jain R, Hachem RR, Morrell MR, et al. Azithromycin is associated with increased survival in lung transplant recipients with bronchiolitis obliterans syndrome. J Heart Lung Transplant 2010;29:531-7. [Crossref] [PubMed]
126. Vos R, Vanaudenaerde BM, Ottevaere A, et al. Long-term azithromycin therapy for bronchiolitis obliterans syndrome: divide and conquer? J Heart Lung Transplant 2010;29:1358-68. [Crossref] [PubMed]
127. Vos R, Vanaudenaerde BM, Verleden SE, et al. A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation. Eur Respir J 2011;37:164-72. [Crossref] [PubMed]
128. Federica M, Nadia S, Monica M, et al. Clinical and immunological evaluation of 12-month azithromycin therapy in chronic lung allograft rejection. Clin Transplant 2011;25:E381-9. [Crossref] [PubMed]
129. Vos R, Vanaudenaerde BM, Verleden SE, et al. Anti-inflammatory and immunomodulatory properties of azithromycin involved in treatment and prevention of chronic lung allograft rejection. Transplantation 2012;94:101-9. [Crossref] [PubMed]
130. Kingah PL, Muma G, Soubani A. Azithromycin improves lung function in patients with post-lung transplant bronchiolitis obliterans syndrome: a meta-analysis. Clin Transplant 2014;28:906-10. [Crossref] [PubMed]
131. Brusselle GG. Are the antimicrobial properties of macrolides required for their therapeutic efficacy in chronic neutrophilic airway diseases? Thorax 2015;70:401-3. [Crossref] [PubMed]
132. Ruttens D, Verleden SE, Vandermeulen E, et al. Prophylactic Azithromycin Therapy After Lung Transplantation: Post hoc Analysis of a Randomized Controlled Trial. Am J Transplant 2016;16:254-61. [Crossref] [PubMed]
133. Vos R, Eynde RV, Ruttens D, et al. Montelukast in chronic lung allograft dysfunction after lung transplantation. J Heart Lung Transplant 2019;38:516-27. [Crossref] [PubMed]
134. Ruttens D, Verleden SE, Demeyer H, et al. Montelukast for bronchiolitis obliterans syndrome after lung transplantation: A randomized controlled trial. PLoS One 2018;13:e0193564. [Crossref] [PubMed]
135. Jain MK, Ridker PM. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat Rev Drug Discov 2005;4:977-87. [Crossref] [PubMed]
136. Ropponen JO, Syrjälä SO, Hollmén M, et al. Effect of simvastatin on development of obliterative airway disease: an experimental study. J Heart Lung Transplant 2012;31:194-203. [Crossref] [PubMed]
137. Johnson BA, Iacono AT, Zeevi A, et al. Statin use is associated with improved function and survival of lung allografts. Am J Respir Crit Care Med 2003;167:1271-8. [Crossref] [PubMed]
138. Li Y, Gottlieb J, Ma D, et al. Graft-protective effects of the HMG-CoA reductase inhibitor pravastatin after lung transplantation--a propensity score analysis with 23 years of follow-up. Transplantation 2011;92:486-92. [Crossref] [PubMed]
139. King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2083-92. [Crossref] [PubMed]
140. Zhou H, Latham CW, Zander DS, et al. Pirfenidone inhibits obliterative airway disease in mouse tracheal allografts. J Heart Lung Transplant 2005;24:1577-85. [Crossref] [PubMed]
141. Ihle F, von Wulffen W, Neurohr C. Pirfenidone: a potential therapy for progressive lung allograft dysfunction? J Heart Lung Transplant 2013;32:574-5. [Crossref] [PubMed]
142. Bennett D, Lanzarone N, Fossi A, et al. Pirfenidone in chronic lung allograft dysfunction: a single cohort study. Panminerva Med 2020;62:143-9. [Crossref] [PubMed]
143. Bos S, De Sadeleer LJ, Vanstapel A, et al. Antifibrotic drugs in lung transplantation and chronic lung allograft dysfunction: a review. Eur Respir Rev 2021;30:210050. [Crossref] [PubMed]
144. Perch M, Besa V, Corris PA, et al. A European Multi‐Center, Randomized, Double‐Blind Trial of Pirfenidone in Bronchiolitis‐Obliterans‐Syndrome Grade 1‐3 in Lung Transplant Recipients (European Trial of Pirfenidone in BOS (EPOS)). J Heart Lung Transplant 2020;39:S12. [Crossref]
145. Reams BD, Musselwhite LW, Zaas DW, et al. Alemtuzumab in the treatment of refractory acute rejection and bronchiolitis obliterans syndrome after human lung transplantation. Am J Transplant 2007;7:2802-8. [Crossref] [PubMed]
146. Vitulo P, Oggionni T, Cascina A, et al. Efficacy of tacrolimus rescue therapy in refractory acute rejection after lung transplantation. J Heart Lung Transplant 2002;21:435-9. [Crossref] [PubMed]
147. Sarahrudi K, Estenne M, Corris P, et al. International experience with conversion from cyclosporine to tacrolimus for acute and chronic lung allograft rejection. J Thorac Cardiovasc Surg 2004;127:1126-32. [Crossref] [PubMed]
148. Valentine VG, Robbins RC, Wehner JH, et al. Total lymphoid irradiation for refractory acute rejection in heart-lung and lung allografts. Chest 1996;109:1184-9. [Crossref] [PubMed]
149. Benden C, Speich R, Hofbauer GF, et al. Extracorporeal photopheresis after lung transplantation: a 10-year single-center experience. Transplantation 2008;86:1625-7. [Crossref] [PubMed]
150. Fuehner T, Simon A, Dierich M, et al. Indicators for steroid response in biopsy proven acute graft rejection after lung transplantation. Respir Med 2009;103:1114-21. [Crossref] [PubMed]
151. Bittner HB, Dunitz J, Hertz M, et al. Hyperacute rejection in single lung transplantation--case report of successful management by means of plasmapheresis and antithymocyte globulin treatment. Transplantation 2001;71:649-51. [Crossref] [PubMed]
152. Hadjiliadis D, Chaparro C, Reinsmoen NL, et al. Pre-transplant panel reactive antibody in lung transplant recipients is associated with significantly worse post-transplant survival in a multicenter study. J Heart Lung Transplant 2005;24:S249-54. [Crossref] [PubMed]
153. Hachem RR. Acute Rejection and Antibody-Mediated Rejection in Lung Transplantation. Clin Chest Med 2017;38:667-75. [Crossref] [PubMed]
154. Roux A, Levine DJ, Zeevi A, et al. Banff Lung Report: Current knowledge and future research perspectives for diagnosis and treatment of pulmonary antibody-mediated rejection (AMR). Am J Transplant 2019;19:21-31. [Crossref] [PubMed]
155. Bery AI, Hachem RR. Antibody-mediated rejection after lung transplantation. Ann Transl Med 2020;8:411. [Crossref] [PubMed]
156. Astor TL, Weill D, Cool C, et al. Pulmonary capillaritis in lung transplant recipients: treatment and effect on allograft function. J Heart Lung Transplant 2005;24:2091-7. [Crossref] [PubMed]
157. Martinu T, Chen DF, Palmer SM. Acute rejection and humoral sensitization in lung transplant recipients. Proc Am Thorac Soc 2009;6:54-65. [Crossref] [PubMed]
158. Morrell MR, Patterson GA, Trulock EP, et al. Acute antibody-mediated rejection after lung transplantation. J Heart Lung Transplant 2009;28:96-100. [Crossref] [PubMed]
159. Stuckey LJ, Kamoun M, Chan KM. Lung transplantation across donor-specific anti-human leukocyte antigen antibodies: utility of bortezomib therapy in early graft dysfunction. Ann Pharmacother 2012;46:e2. [Crossref] [PubMed]
160. Otani S, Davis AK, Cantwell L, et al. Evolving experience of treating antibody-mediated rejection following lung transplantation. Transpl Immunol 2014;31:75-80. [Crossref] [PubMed]
161. Snyder LD, Gray AL, Reynolds JM, et al. Antibody desensitization therapy in highly sensitized lung transplant candidates. Am J Transplant 2014;14:849-56. [Crossref] [PubMed]
162. Levine DJ, Glanville AR, Aboyoun C, et al. Antibody-mediated rejection of the lung: A consensus report of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2016;35:397-406. [Crossref] [PubMed]
163. Ensor CR, Yousem SA, Marrari M, et al. Proteasome Inhibitor Carfilzomib-Based Therapy for Antibody-Mediated Rejection of the Pulmonary Allograft: Use and Short-Term Findings. Am J Transplant 2017;17:1380-8. [Crossref] [PubMed]
164. Durandy A, Kaveri SV, Kuijpers TW, et al. Intravenous immunoglobulins--understanding properties and mechanisms. Clin Exp Immunol 2009;158:2-13. [Crossref] [PubMed]
165. Muller YD, Aubert JD, Vionnet J, et al. Acute Antibody-mediated Rejection 1 Week After Lung Transplantation Successfully Treated With Eculizumab, Intravenous Immunoglobulins, and Rituximab. Transplantation 2018;102:e301-3. [Crossref] [PubMed]
166. Neumann J, Tarrasconi H, Bortolotto A, et al. Acute humoral rejection in a lung recipient: reversion with bortezomib. Transplantation 2010;89:125-6. [Crossref] [PubMed]
167. Baum C, Reichenspurner H, Deuse T. Bortezomib rescue therapy in a patient with recurrent antibody-mediated rejection after lung transplantation. J Heart Lung Transplant 2013;32:1270-1. [Crossref] [PubMed]
168. Gauthier JM, Hachem RR, Kreisel D. Update on Chronic Lung Allograft Dysfunction. Curr Transplant Rep 2016;3:185-91. [Crossref] [PubMed]
169. Moniodis A, Townsend K, Rabin A, et al. Comparison of extracorporeal photopheresis and alemtuzumab for the treatment of chronic lung allograft dysfunction. J Heart Lung Transplant 2018;37:340-8. [Crossref] [PubMed]
170. Trindade AJ, Thaniyavarn T, Townsend K, et al. Alemtuzumab as a Therapy for Chronic Lung Allograft Dysfunction in Lung Transplant Recipients With Short Telomeres. Front Immunol 2020;11:1063. [Crossref] [PubMed]
171. January SE, Fester KA, Bain KB, et al. Rabbit antithymocyte globulin for the treatment of chronic lung allograft dysfunction. Clin Transplant 2019;33:e13708. [Crossref] [PubMed]
172. O'Hagan AR, Stillwell PC, Arroliga A, et al. Photopheresis in the treatment of refractory bronchiolitis obliterans complicating lung transplantation. Chest 1999;115:1459-62. [Crossref] [PubMed]
173. Morrell MR, Despotis GJ, Lublin DM, et al. The efficacy of photopheresis for bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant 2010;29:424-31. [Crossref] [PubMed]
174. Jaksch P, Scheed A, Keplinger M, et al. A prospective interventional study on the use of extracorporeal photopheresis in patients with bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant 2012;31:950-7. [Crossref] [PubMed]
175. Baskaran G, Tiriveedhi V, Ramachandran S, et al. Efficacy of extracorporeal photopheresis in clearance of antibodies to donor-specific and lung-specific antigens in lung transplant recipients. J Heart Lung Transplant 2014;33:950-6. [Crossref] [PubMed]
176. Del Fante C, Scudeller L, Oggionni T, et al. Long-Term Off-Line Extracorporeal Photochemotherapy in Patients with Chronic Lung Allograft Rejection Not Responsive to Conventional Treatment: A 10-Year Single-Centre Analysis. Respiration 2015;90:118-28. [Crossref] [PubMed]
177. Benden C, Haughton M, Leonard S, et al. Therapy options for chronic lung allograft dysfunction-bronchiolitis obliterans syndrome following first-line immunosuppressive strategies: A systematic review. J Heart Lung Transplant 2017;36:921-33. [Crossref] [PubMed]
178. Fisher AJ, Rutherford RM, Bozzino J, et al. The safety and efficacy of total lymphoid irradiation in progressive bronchiolitis obliterans syndrome after lung transplantation. Am J Transplant 2005;5:537-43. [Crossref] [PubMed]
179. Verleden GM, Lievens Y, Dupont LJ, et al. Efficacy of total lymphoid irradiation in azithromycin nonresponsive chronic allograft rejection after lung transplantation. Transplant Proc 2009;41:1816-20. [Crossref] [PubMed]
180. Lebeer M, Kaes J, Lambrech M, et al. Total lymphoid irradiation in progressive bronchiolitis obliterans syndrome after lung transplantation: a single-center experience and review of literature. Transpl Int 2020;33:216-28. [Crossref] [PubMed]