Maintenance immunosuppression following lung transplantation

INTRODUCTION — Maintenance immunosuppressive therapy is administered to all lung transplant recipients to help prevent acute and chronic rejection and the loss of the lung allograft. [1]. Substantial progress has been made in developing immunosuppressive regimens to prevent acute and chronic rejection, while trying to reduce the side effects of immunosuppression [2]. However, despite improvements in immunosuppressive therapy, acute and chronic transplant rejection remain important obstacles to successful lung transplantation.

The protocols for immunosuppressive therapy following lung transplantation can be divided into three general categories: induction, maintenance, and treatment of rejection. Strategies for maintenance immunosuppression in the lung transplant recipient will be reviewed here. The role of induction agents in immunosuppression, general issues related to lung transplantation, the immunology of solid organ transplantation, and the diagnosis and treatment of acute and chronic lung transplant rejection are discussed separately. (See "Induction immunosuppression following lung transplantation" and "Lung transplantation: An overview" and "Transplantation immunobiology" and "Evaluation and treatment of acute cellular lung transplant rejection" and "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome".)

GENERAL PRINCIPLES — Three general principles underlie immunosuppressive therapy following lung transplantation:

●The first principle is that immune reactivity and the tendency toward acute graft rejection are highest early (within the first three to six months) after graft implantation and decrease with time. Thus, most regimens employ the highest intensity of immunosuppression immediately after surgery and decrease the intensity of therapy over the first year, eventually settling on the lowest maintenance levels of immunosuppression that are compatible with preventing graft rejection while minimizing drug toxicities.

●The second principle is to use low doses of several drugs with non-overlapping toxicities in preference over higher (and more toxic) doses of fewer drugs whenever feasible. Combination regimens are also better able to block the complex immunological cascade that leads to allograft rejection.

●The third principle is to avoid over-immunosuppression, because it leads to a myriad of undesirable effects including susceptibility to infection and malignancy. (See "Infection in the solid organ transplant recipient" and "Malignancy after solid organ transplantation" and "Treatment and prevention of post-transplant lymphoproliferative disorders".)

There is no consensus regarding the optimal maintenance regimen for immunosuppression following lung transplantation [2]. In addition, until the US Food and Drug Administration (FDA) approval of tacrolimus (TAC) in 2021, there were no FDA-approved immunosuppressive medications for use in lung transplantation.

Based on data from case series and clinical experience, maintenance immunosuppression usually includes a combination of three drugs: a glucocorticoid (prednisone), a calcineurin inhibitor (CNI; cyclosporine [CsA] or TAC), and a nucleotide blocking agent (mycophenolate mofetil [MMF] or azathioprine) (table 1). The mTOR inhibitors (sirolimus and everolimus) are alternative agents used in lung transplantation maintenance immunosuppression and have been used as replacements for the nucleotide blocking agents or, less commonly, for CNIs. The maintenance immunosuppressive regimen used in a given individual is based upon side effect profile and tolerability of medication. Because of preliminary data suggesting an excessive rate of infectious complications in older patients (>65 years), some centers elect to use a less intensive immunosuppressive regimen for this cohort [3]. In the 2019 registry report from the International Society for Heart and Lung Transplantation (ISHLT), 62 percent of all lung transplant recipients were on a combination of TAC, mycophenolate, and prednisone a year after lung transplantation [4].

Many drugs used in immunosuppression are metabolized by the cytochrome P450 (CYP450) enzyme system in the liver. These, along with other drugs that induce and inhibit this enzyme system are listed in the table, along with suggestions for alternatives, additional monitoring, and dose adjustments (table 2).

AGENTS FOR MAINTENANCE THERAPY

Glucocorticoids — Maintenance therapy for lung transplantation has always included glucocorticoids. Glucocorticoids inhibit both humoral and cell-mediated immunity. The principal effect of glucocorticoids is to turn off gene transcription of multiple inflammatory genes [5]. The result is a decrease in the inflammatory response through reduced production of cytokines, interleukin (IL)-1, IL-2, IL-6, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha [6]. (See "Transplantation immunobiology", section on 'Molecular mechanisms of T cell activation'.)

There is considerable variability among centers related to glucocorticoid protocols but several general trends can be highlighted. An initial intravenous dose of 500 to 1000 mg of methylprednisone is typically administered intraoperatively at the time of reperfusion of the allograft(s) (table 1) [7]. Subsequently, prednisone is given orally at 0.5 to 1 mg/kg per day, or an equivalent dose of methylprednisolone is administered intravenously until the patient is able to take oral medications.

Prednisone is tapered to 5 to 10 mg/day during the first year post-lung transplant; in most patients, this goal can be achieved within three months post-transplant. Episodes of acute rejection are typically treated with high-dose parenteral glucocorticoids, which are usually tapered back to the maintenance dose over several weeks. The majority of patients stay on prednisone for life, although a few patients are able to be successfully weaned off [8,9]. (See "Evaluation and treatment of acute cellular lung transplant rejection", section on 'High-dose glucocorticoids'.)

Glucocorticoids are associated with a number of side effects including, but not limited to, diabetes, fluid retention, hypertension, emotional lability, poor wound healing, osteoporosis, cataracts, and susceptibility to infection. Efforts have been made to minimize glucocorticoid doses in the lung transplantation population due to these side effects. (See "Major adverse effects of systemic glucocorticoids".)

Calcineurin inhibitors — Calcineurin inhibitors (CNIs) include tacrolimus (TAC) and cyclosporine (CsA). CNIs are viewed as essential components of maintenance immunosuppression following lung transplantation, and protocols without a CNI generally are not recommended, due to insufficient evidence of their efficacy. The overwhelming majority of centers use TAC as part of the maintenance immunosuppression following lung transplantation [10].

Tacrolimus — TAC (FK-506) was approved by the US Food and Drug Administration (FDA) in July 2021 for use in lung transplantation and is used for maintenance immunosuppression by more than 90 percent of lung transplant recipients [10,11]. TAC binds with the cytoplasmic immunophilin, FK binding protein 12 (FKBP-12), and inactivates calcineurin, thus inhibiting both IL-2 and interferon-gamma. Ultimately, T cell activation and proliferation are inhibited. TAC is more potent in its immunosuppressive properties than CsA and slightly less nephrotoxic.

●Dosing and administration – Sublingual or oral dosing is generally preferred, because intravenous (IV) administration of TAC has been associated with infusion reactions (including anaphylaxis) and an increased risk of neurotoxicity and nephrotoxicity compared with oral use. Sublingual administration of tacrolimus (ie, using the powder removed from immediate-release capsules) appears to have greater bioavailability than swallowed pills in lung transplant patients [12-14].

•For patients receiving the initial dose of TAC sublingually, the usual dose is approximately 0.04 to 0.05 mg/kg/day in two divided doses (eg, 1 to 2 mg sublingually every 12 hours) [12,13]. A larger or smaller initial dose is selected based on considerations such as concomitant medications, age, weight, and kidney and liver function. Subsequent adjustments are dictated by whole blood trough levels. Additional monitoring and dose adjustment are needed when converting to or from sublingual to oral administration; some centers use a conversion ratio of 1 mg sublingual to 2 mg oral TAC.

•For patients receiving the initial dose of TAC intravenously, the usual dose is 0.03 to 0.05 mg/kg/day administered by continuous infusion over 24 hours (although some institutions use an intermittent infusion given every 12 hours). When switching from IV to oral or sublingual dosing, the first dose of oral or sublingual therapy should be given 8 to 12 hours after discontinuing the IV infusion.

•For patients needing to switch from oral to IV administration (eg, during an intercurrent illness), the total daily IV dose is approximately one-third or less than the daily oral dose; this dose may be decreased further if the patient has acute kidney injury or another process that would alter TAC metabolism.

TAC has poor oral absorption, variable bioavailability, and a narrow therapeutic window (table 3) [15]. To improve absorption, patients should take the drug on an empty stomach or two hours after a meal. Careful monitoring of blood levels is essential. In general, transplant centers aim for a TAC trough target level of 10 to 15 ng/mL for months 1 to 3, 8 to 13 ng/mL for months 4 to 12, and 6 to 8 ng/mL after the first 12 months, but target levels often vary based on center practice and clinical circumstances [11]. For example, the target level may be adjusted to be higher when there is evidence of allograft rejection or lower when there is infection or TAC-related toxicity.

TAC is cleared in the bile after extensive metabolism in the liver by CYP 3A4, and thus there are substantial drug-drug interactions with other medications metabolized via CYP 3A4 (table 2 and table 4). Additional information on drug interactions is available from the drug interactions program provided by UpToDate. (See "Pharmacology of cyclosporine and tacrolimus".)

Kidney dysfunction is a common dose-related side effect and is a serious problem with long-term TAC treatment. In patients who develop kidney insufficiency, TAC levels should be reduced. Other potential side effects of TAC are described separately. (See "Cyclosporine and tacrolimus nephrotoxicity" and "Pharmacology of cyclosporine and tacrolimus" and "Pharmacology of cyclosporine and tacrolimus", section on 'Side effects'.)

●Efficacy – Published data in support of TAC following lung transplantation is limited. In a retrospective registry study, 26,800 lung transplant recipients (25,355 adults; 725 children) were assessed for graft failure or death one year after transplant [16]. The risk of graft failure was lower in adults treated with TAC plus mycophenolate (8.6 percent) compared with CsA plus mycophenolate (13.7 percent) or CsA plus azathioprine (11.2 percent).

Cyclosporine — The success of CsA was first demonstrated in lung transplantation in 1983 [1,17]. CsA was revolutionary in the field of organ transplantation because it was the first T cell selective drug [18]. CsA binds to intracellular proteins (cyclophilins) that inhibit calcineurin, a protein phosphatase that is critical for T cell activation. Through CNI, transcription of IL-2 and several other cytokines is inhibited. CsA, therefore, inhibits activation and proliferation of T lymphocytes [15,19].

In general, an initial dose of CsA of 2 to 3 mg/kg is administered at the time of transplantation as a 24-hour infusion or one-half the dose as a four-hour infusion twice a day and continued until the patient is able to take oral medication; dosing is adjusted per target concentrations (table 1). The maintenance oral dose is 3 to 5 mg/kg twice a day, orally as a tablet or a suspension. CsA can be administered IV, for those unable to take oral medication. The IV dose is approximately 30 percent of the usual oral dose due to improved bioavailability.

Similar to TAC, CsA has significant inter- and intra-individual absorption variability and a narrow therapeutic window, and therefore monitoring of drug levels is crucial [20]. Trough levels are targeted at 250 to 350 ng/mL during the initial post-transplant year and 200 to 300 ng/mL subsequently. Because trough levels correlate less well with the pharmacokinetics of CsA, some centers base dosing on CsA levels drawn at two or three hours post-dose (called C2 and C3, respectively) as these are more reflective of exposure to CsA over time. The goal is to maintain the C2 levels between 900 and 1200 ng/mL for the first year post-transplant. CsA is metabolized in the liver by cytochrome P450 3A (CYP 3A4), and thus there are numerous drug-drug interactions (table 2 and table 4). Several CYP 3A4 inhibitors also inhibit the P-glycoprotein efflux pump, which may increase the magnitude of the interaction. Additional information on drug interactions is available from the drug interactions program provided by UpToDate. (See "Pharmacology of cyclosporine and tacrolimus".)

The original commercial preparation of CsA, Sandimmune, has poor and unpredictable absorption due to its highly lipophilic nature and dependence on bile for absorption (table 3) [21]. The newer, microemulsion formulation, Neoral (Novartis), has improved bioavailability, more consistent oral absorption, and more reproducible pharmacokinetic behavior [22]. As a result, Neoral, Sandimmune, and generic formulations should not be used interchangeably, and vigilant pharmacokinetic monitoring should accompany any change in formulation [23].

Kidney dysfunction is a common dose-related side effect and is a serious problem with long-term treatment. Other potential side effects of CsA are described separately. (See "Cyclosporine and tacrolimus nephrotoxicity" and "Pharmacology of cyclosporine and tacrolimus", section on 'Side effects'.)

Tacrolimus versus cyclosporine — Several small retrospective studies as well as randomized trials suggest that TAC is associated with a decreased incidence of acute rejection and bronchiolitis obliterans syndrome when compared with CsA [24]. As a result, most lung transplant centers use TAC rather than CsA as part of initial maintenance immunosuppression regimens for lung transplantation. Supportive evidence comes from the studies outlined below that report a reduction in acute and chronic lung allograft rejection when TAC is used in the regimen instead of CsA. Of note, no statistically significant differences in survival were noted in these studies.

●In a randomized trial of 133 lung transplant patients, fewer patients in the TAC/azathioprine/glucocorticoid group developed bronchiolitis obliterans syndrome (BOS) compared with the CsA/azathioprine/glucocorticoid group (22 versus 38 percent; p = 0.025) [25].

●A randomized trial compared the efficacy of TAC versus CsA in 90 lung transplantation patients who also received azathioprine and prednisone; those treated with TAC were significantly less likely to develop acute rejection or lymphocytic bronchitis (41 versus 63 percent) [26].

●A randomized multicenter trial compared TAC to CsA when combined with mycophenolate mofetil (MMF) and prednisone in 149 lung transplant recipients and found a reduction in three year BOS incidence (12 percent with TAC and 21 percent with CsA, p = 0.037), but did not show any difference in acute rejection or survival [27]. Cytolytic induction therapy was not used in these patients.

In contrast to the above studies, another study evaluated 74 lung transplant recipients, who received induction therapy with rabbit antithymocyte globulin (rATG) and were randomly assigned to the combination of CsA/MMF/glucocorticoids or the combination of tacrolimus/MMF/glucocorticoids [28]. No significant difference was noted in the incidence of acute rejection or survival. Drug-related adverse effects were similar in number although different in type; hypertension was more common in the CsA group, while new-onset diabetes mellitus was more common in the TAC group.

Taken together, these studies lean in favor of TAC and reflect clinical practice and registry outcome data. According to the 2019 Registry of the ISHLT, CsA combined with azathioprine or MMF was associated with increased acute rejection episodes between discharge and one-year follow up compared with corresponding TAC based regimens [10].

Nucleotide blocking agents — MMF and azathioprine (AZA) are nucleotide blocking agents that are common agents in maintenance immunosuppression regimens following lung transplantation. The choice between MMF and AZA is generally made by the individual center [7,29-31].

Mycophenolate mofetil — Mycophenolate mofetil (MMF) is a fermentation product of Penicillium brevicompactum and related fungi. After oral administration, MMF is rapidly absorbed and converted in the liver to its active form, mycophenolic acid (MPA). MPA depletes guanosine nucleotides in T and B lymphocytes, thus inhibiting proliferation of T and B cells and the glycosylation and expression of adhesion molecules [7,32]. Approximately 70 percent of lung transplant recipients are receiving MMF as a core constituent of their maintenance immunosuppression [10].

The dose of MMF is 1000 to 1500 mg orally given twice daily, starting within 72 hours after transplantation. Dosing information is provided in the table (table 1). Due to the potential for myelosuppression, careful monitoring of peripheral blood counts should be performed on a regular basis. Other major side effects include diarrhea, nausea, and abdominal pain.

MMF is available as a capsule and as a powder for intravenous use after reconstitution; mycophenolate sodium (MPS, Myfortic) contains mycophenolic acid in a delayed release oral tablet. MPS has been found to be comparable in efficacy to the previous formulation of MMF in kidney and heart transplantation [33,34]. The following conversions between mycophenolate mofetil (MMF) and mycophenolate sodium (MPS) should provide equimolar amounts of MPA:

●1000 mg MMF = 720 mg MPS

●1500 mg MMF = 1080 mg MPS

Monitoring of mycophenolic acid (MPA) serum levels is not routinely performed by the majority of centers. However, MPA levels can be monitored especially in cases where over immunosuppression is suspected. The therapeutic range for MPA levels is between 1.0 and 3.5 mcg/mL. There are, however, a number of drugs and agents that interact with MPA, including birth control pills, aluminum and magnesium antacids, acyclovir, ganciclovir, azathioprine, and cholestyramine [35]. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Drug interactions'.)

Azathioprine — Azathioprine (AZA) is an anti-metabolite that has been used in lung transplantation in combination with glucocorticoids since the 1960s. By preventing the de novo synthesis of purines and thus interfering with RNA and DNA synthesis, AZA inhibits the replication of T and B cells. In addition, AZA metabolites have been shown to turn the costimulatory signal CD28 into an apoptotic signal, resulting in lymphocyte depletion [35-37].

AZA is metabolized to mercaptopurine (MP; also known as 6-mercaptopurine) by glutathione, and then converted to 6-thiouric acid, 6 methyl-MP and 6-thioguanine (6TG) by thiopurine S-methyltransferase (TPMT). Approximately 10 percent of the population possesses a polymorphism of TPMT that causes low enzyme activity and potential acute AZA-induced myelosuppression. Some transplant centers assess TPMT levels at the time of listing for transplant or prior to initiation of the drug; AZA is either avoided or used with dose reduction in patients with known TPMT deficiency. (See "Thiopurines: Pretreatment testing and approach to therapeutic drug monitoring for adults with inflammatory bowel disease", section on 'Summary and recommendations'.)

AZA is typically initiated on the first day after transplantation at a dose of 1 to 2 mg/kg per day up to a maximum of 200 mg per day in a single dose (table 1). Dosing is equivalent for both intravenous and oral administration. Myelosuppression, hepatotoxicity, and pancreatitis are potential side effects of AZA and require close monitoring. AZA should not be used in combination with allopurinol, as the combination can lead to profound and sustained myelosuppression.

Mycophenolate mofetil versus azathioprine — Data from other solid organ transplants support the use of MMF over azathioprine, but the literature in lung transplantation is scant and conflicting.

Small case series have suggested superiority of MMF to AZA in preventing acute rejection [38-40]. However, two randomized trials comparing MMF to AZA in lung transplantation did not show a clear superiority of MMF [30,31]. One of these studies was a randomized, multicenter trial that compared MMF to AZA in 315 lung transplant recipients in a CsA-based regimen following anti-thymocyte globulin (ATG) induction [31]. At interim analysis, 12-month survival was better in the MMF group versus AZA (88.1 versus 79.1 percent, respectively p = 0.038). By three years, however, survival was not significantly different between the two groups. Additionally, the rates of BOS and biopsy-proven acute rejection were not different between the two groups at the one-year interim analysis or at three years. Infection and malignancy rates were likewise similar in both groups. Importantly, a significantly greater number of patients withdrew from the AZA group, primarily for lack of therapeutic response, which may have masked differences between the two groups.

In ISHLT registry data, acute rejection requiring treatment within the first post-transplant year occurred in 33 percent of those receiving the combination of MMF/cyclosporine compared with 54 percent among those on AZA/cyclosporine [10]. The advantage of MMF over AZA may depend on the associated CNI, as the difference in effect on acute rejection between MMF and AZA was less apparent when the drugs were combined with TAC. Acute rejection occurred in 24 percent of those on MMF/TAC compared with 29 percent among those on AZA/TAC [10].

Despite the scant data, MMF has evolved as the preferred maintenance agent, currently utilized in approximately 80 percent of lung transplant recipients [10]. AZA is the primary antimetabolite of choice for patients interested in becoming pregnant, given the teratogenicity and risk of spontaneous abortion associated with MMF [41].

mTOR inhibitors — Sirolimus and everolimus are inhibitors of the mechanistic target of rapamycin (mTOR, also known as the mammalian target of rapamycin). They have a similar structure to the calcineurin inhibitors, but exert their immunosuppressive effects through calcineurin-independent mechanisms. (See 'Calcineurin inhibitors' above and "Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors", section on 'Mechanism of action'.)

Sirolimus/everolimus — Sirolimus is a macrolide antibiotic, derived from the actinomycete Streptomyces hygroscopicus, with potent antifungal and immunosuppressive properties [42-44]. Everolimus is a derivative of sirolimus. mTOR inhibitors exert their immunosuppressive effect by binding to FKBP12, a member of the immunophilin protein family. The mTOR inhibitor-FKBP12 complex blocks the mechanistic target of rapamycin (previously mammalian target of rapamycin, mTOR), thereby interrupting DNA and protein synthesis and proliferation of T, NK, and B cells [45,46]. Both drugs also inhibit fibroblast proliferation resulting in impaired wound healing [47].

Patient selection — mTOR inhibitors are typically reserved for patients who do not tolerate the nucleotide blocking agents or have allograft rejection that is refractory to nucleotide blocking agents (see 'Nucleotide blocking agents' above). They have also been used in the setting of progressive kidney insufficiency to permit reduction in CNI dosing or as part of a CNI-free regimen [48]. The latter strategy must be utilized with caution as the ability of a CNI-free regimen to prevent rejection is only anecdotally supported.

Dosing — The usual initial dose of sirolimus is 2 mg per day orally; everolimus is initiated at 1.5 mg twice daily. The therapeutic ranges for sirolimus and everolimus blood levels are 5 to 15 ng/mL and 3 to 12 ng/mL, respectively. Dosing information is provided in the table (table 1). Due to synergistic effects, the dose of concomitant calcineurin inhibitors should be decreased by one-half after starting sirolimus or everolimus.

Both sirolimus and everolimus are metabolized by the cytochrome p450 enzyme system, thus dose adjustment is necessary in the presence of hepatic dysfunction and with concomitant use of other agents metabolized by the same pathway. Inhibitors and inducers of the P450 enzyme system should be added cautiously to the recipient's regimen; coadministration of azole anti-fungal drugs with mTOR inhibitors requires close attention (table 2 and table 4). (See "Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors", section on 'Drug interactions'.) Additional information on drug interactions is available from the drug interactions program provided by UpToDate.

Adverse effects — Several fatal cases of anastomotic bronchial dehiscence have been reported when sirolimus was used in the first 30 to 90 days following lung transplantation. Thus, initiation of sirolimus or everolimus should be delayed until after the bronchial anastomosis is completely healed [49-51]. (See "Airway complications after lung transplantation", section on 'Delaying use of sirolimus'.)

Other substantial adverse effects of the mTOR inhibitors include impaired wound healing, infection, hyperlipidemia, and cytopenias [49-53]. The combination of sirolimus and CsA has caused synergistic nephrotoxicity in animals, although sirolimus is minimally nephrotoxic when used alone [54]. (See "Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors", section on 'Adverse effects'.)

Sirolimus may be associated with an increased risk of venous thromboembolism (VTE). In a study of 181 lung transplant recipients randomly assigned to TAC, sirolimus, and prednisone compared with those assigned to TAC, azathioprine, and prednisone, those in the sirolimus group had an increased risk of VTE (HR 5.2, 95% CI 1.4-19.5) [55]. Additional study is needed to corroborate these findings.

Sirolimus has been implicated in drug-induced interstitial pneumonitis following kidney, liver, and lung transplantation [56-58]. Various injury patterns have been reported including organizing pneumonia, lymphocytic interstitial infiltrates, and alveolar hemorrhage [58-60]. Discontinuation of sirolimus typically results in clinical improvement in pneumonitis within two weeks; glucocorticoids are used in severe or refractory cases.

Azathioprine versus sirolimus/everolimus — Sirolimus and everolimus have been compared with azathioprine in two randomized trials. While reduced rates of acute rejection were reported in one trial employing everolimus, significantly higher rates of adverse events were associated with sirolimus and everolimus in both trials [52,53].

●In one trial, 213 patients who had undergone lung transplantation were randomly assigned to receive everolimus (3 mg/day) or azathioprine (1 to 3 mg/kg per day) in combination with CsA and glucocorticoids as maintenance therapy [52]. In the first year, everolimus treatment resulted in fewer episodes of acute rejection (8 versus 32 percent) and less deterioration (9 versus 20 percent) in forced expiratory volume in one second (FEV₁), a marker for chronic rejection. However, only the difference in acute rejection rates remained significant after two years. Everolimus treatment resulted in more adverse effects including serious bacterial and fungal infections, pneumonia, hyperlipidemia, anemia, and thrombocytopenia.

●In a multicenter trial, 181 lung transplant recipients were randomly assigned to continue azathioprine or switch to sirolimus at 90 days in a tacrolimus based immunosuppressive regimen [53]. At 1 year after transplantation, there was no significant difference in the incidence of grade A acute rejection (table 5), bronchiolitis obliterans syndrome (BOS), or graft survival between the two study groups. There was a higher rate of adverse events leading to early discontinuation of sirolimus (64 percent) compared with azathioprine (49 percent) during the course of this study.

Mycophenolate versus sirolimus/everolimus — Randomized trial data suggest that mycophenolate and everolimus (started 30 to 90 days after transplant) have comparable efficacy in prevention of BOS, but the rates of rejection and adverse events may be greater with mycophenolate. Observational data suggest potential superiority of sirolimus over MMF.

●In a multicenter, randomized trial comparing de novo mycophenolate sodium with delayed administration of everolimus (initiated 30 to 90 days post-transplant) in a CsA-based immunosuppressive regimen, there was no difference in three year freedom from BOS Grade 1 between the two arms [61]. More episodes of biopsy-proven rejection, leukopenia, diarrhea, cytomegalovirus (CMV) infection, and venous thromboembolism were noted in the mycophenolate group.

●In a separate randomized, open-label trial, 190 patients were assigned to MMF or everolimus starting on day 28 post-transplant; both regimens were combined with CsA and glucocorticoids [62]. No difference was found in BOS-free survival or kidney function at two years.

●In a retrospective cohort study utilizing data from the United Network for Organ Sharing (UNOS) registry, 219 patients receiving sirolimus were compared with 5782 patients receiving MMF [63]. Conditioned on one-year survival and excluding patients with malignancy or chronic rejection identified in the first year, there was a significant improvement in survival identified in patients receiving sirolimus compared with MMF.

No role for everolimus as add-on to standard calcineurin-based regimens — Calcineurin inhibitor (CNI) use is associated with significant risk for nephrotoxicity, leading to evaluation of everolimus use to lower the dose of CNI. This approach does not appear to improve on the safety of standard regimens and may worsen outcomes. (See "Cyclosporine and tacrolimus nephrotoxicity" and "Pharmacology of cyclosporine and tacrolimus" and "Pharmacology of cyclosporine and tacrolimus", section on 'Side effects'.)

●A multicenter randomized trial of 120 patients assessed the impact on kidney function of early addition of everolimus to standard CNI-based immunosuppression regimens to reduce the intensity of CNI therapy [64]. After five years, there were no significant differences in CLAD-free survival, kidney function, or prevalence of end-stage kidney disease between the groups [65]. Compared with patients receiving standard CNI therapy, those receiving add-on everolimus demonstrated increased thrombotic events (24 versus 11 percent) and a trend towards increased mortality (23 versus 14 percent).

Alternative agents and regimens — While CNIs remain the backbone of immunosuppression maintenance regimens for the majority of lung transplant recipients, complications associated with their use commonly compromise post-transplant outcomes (see "Cyclosporine and tacrolimus nephrotoxicity" and "Pharmacology of cyclosporine and tacrolimus", section on 'Side effects'). This has prompted an ongoing search for potential alternatives, typically based on regimens identified in other solid organ transplant populations.

Macrolides — Macrolides have been shown to have immunomodulatory properties and have beneficial effects on pulmonary function in patients with diffuse panbronchiolitis and cystic fibrosis. In lung transplant recipients, macrolides may be effective in the prevention of bronchiolitis obliterans syndrome (BOS). A randomized trial that included 83 lung transplant recipients showed that the addition of azithromycin to maintenance immunosuppression led to an improvement in BOS free survival at two years [66]. These data are promising especially in light of the excellent safety profile of azithromycin and other macrolides [67]. A trial of azithromycin is now recommended as part of the diagnostic and therapeutic algorithm for chronic lung allograft dysfunction (CLAD) [68]. The role of azithromycin in the treatment of BOS is discussed separately. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome", section on 'New onset BOS'.)

Belatacept — Belatacept is a costimulatory antagonist, binding to the CD80 and CD86 receptors on antigen presenting cells, preventing binding to CD28 on the T cell. This inhibition limits replication and activation in response to antigen presenting cells. Belatacept is noninferior to CNIs for preventing acute rejection in kidney transplant recipients. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy".)

However, one pilot randomized trial in lung transplant recipients showed increased mortality with a belatacept-based regimen compared with a typical transplant regimen [69]. Among patients assigned to belatacept, tacrolimus, and prednisone followed by belatacept, mycophenolate, and prednisone, mortality was 38 percent compared to 0 percent with mycophenolate, tacrolimus, and prednisone; the trial was terminated early secondary to evidence for harm. Other data for safety and efficacy of belatacept in lung transplantation are limited to case reports and case series [70-72]. Further study is required before belatacept can be used for replacement or dose-reduction of CNIs after lung transplantation.

MONITORING AND ADJUSTING MAINTENANCE THERAPY — Following discharge from the hospital after lung transplantation, patients are monitored on an ongoing basis for evidence of lung transplant rejection, adverse effects of medications, adequacy of immunosuppression and immunosuppressive drug levels.

The exact timing of routine lab testing following lung transplantation varies among transplant programs. A typical monitoring program includes complete blood counts, liver function tests, blood urea nitrogen, creatinine, potassium, magnesium, glucose, calcineurin inhibitor (CNI) and/or mammalian target of rapamycin (mTOR) inhibitor levels, and cytomegalovirus viral load (eg, polymerase chain reaction) weekly for the first month, then biweekly for two months, then monthly for three months, and then every three months (table 6). A lipid panel is assessed monthly for the first few months and then every three to six months. (See "Prevention of cytomegalovirus infection in lung transplant recipients", section on 'Diagnostic tests'.)

Unfortunately, laboratory testing that would accurately and directly assess the degree of immunosuppression is not available, so monitoring depends on indirect measures, such as drug levels and cell counts, and also graft monitoring by pulmonary function tests and biopsy. Evaluation for acute and chronic lung transplant rejection is discussed separately. (See "Evaluation and treatment of acute cellular lung transplant rejection", section on 'Diagnosis' and "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome", section on 'Diagnosis'.)

In general, maintenance immunosuppression is decreased after the first post-transplant year. Decisions to taper medications are made on a case by case basis depending on the recipient’s history of rejection episodes and adverse effects from the medications. In lung recipients who remain stable without acute rejection or chronic lung allograft dysfunction, the CNI and glucocorticoid doses may be reduced. Additionally, immunosuppression may be reduced in lung recipients with persistent or virulent infections. (See "Evaluation and treatment of acute cellular lung transplant rejection" and "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome".)

TREATMENT OF REJECTION — Regardless of the maintenance therapy used, lung transplant recipients may experience at least one episode of acute rejection, most commonly in the first several months after transplantation. Chronic rejection (chronic lung allograft dysfunction) remains a major cause of morbidity and mortality in this population. The management of acute and chronic rejection is discussed in detail separately. (See "Evaluation and treatment of acute cellular lung transplant rejection" and "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome".)

PREVENTION OF OPPORTUNISTIC INFECTION — Opportunistic infection is a major side effect of immunosuppression for organ transplantation. Regimens for prophylaxis against bacterial, fungal, and viral infections post-transplant are discussed separately. (See "Bacterial infections following lung transplantation", section on 'Prophylaxis' and "Bacterial infections following lung transplantation", section on 'Vaccination' and "Viral infections following lung transplantation", section on 'Summary and recommendations' and "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients" and "Fungal infections following lung transplantation", section on 'Prophylaxis'.)

FUTURE DIRECTIONS — Efforts are being made to identify less toxic and more effective agents for posttransplant immunosuppression regimens.

●Focused immunosuppression and improved monitoring – A goal for future immunosuppressive regimens is a better understanding of their effects on inhibition of activation of T cells, depletion of alloreactive T cells, and protection of T regulatory cells and their function, in order to promote tolerance [73]. In addition, improved immune monitoring is a much needed tool in order to optimize current immunosuppressive strategies in lung transplantation. Monitoring quantitative levels of ubiquitous viruses, such as Torque Teno Virus, that vary in response to immune state is an intriguing future guide for individualizing immunosuppression regimens [74,75]. (See "TT virus and other anelloviruses".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lung transplantation".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topic (see "Patient education: Lung transplant (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Overview – Maintenance immunosuppressive regimens after lung transplantation vary according to transplant center experience and recipient characteristics (eg, rejection history and individual drug tolerability). To reduce toxicity and achieve adequate suppression of allograft rejection, a combination of immunosuppressive agents is used. (See 'General principles' above.)

For all lung transplant recipients, we recommend administration of maintenance immunosuppressive therapy to reduce the risk of acute and chronic rejection (Grade 1A). Maintenance regimens typically consist of three drugs, including a glucocorticoid, a calcineurin inhibitor (CNI; cyclosporine, tacrolimus), and a nucleotide blocking agent (azathioprine, mycophenolate mofetil) (table 1). However, among these choices, the optimal regimen is not known. (See 'General principles' above.)

●Systemic glucocorticoid – The typical initial dose of glucocorticoid is administered perioperatively as the equivalent of methylprednisolone 500 to 1000 mg, intravenously (IV). Subsequently, prednisone is given orally at 0.5 to 1 mg/kg per day, or an equivalent dose IV. Dosing information is provided in the table (table 1). (See 'Glucocorticoids' above.)

●CNIs— CNIs are essential components of maintenance immunosuppression following lung transplantation. We suggest choosing tacrolimus rather than cyclosporine (Grade 2C), based on the slightly better adverse effect profile of tacrolimus and limited data suggesting possible greater efficacy with tacrolimus. Dosing and pharmacokinetic information is provided in the tables (table 1 and table 3). (See 'Tacrolimus versus cyclosporine' above.)

●Nucleotide blocking agents – When selecting a nucleotide blocking agent for the initial maintenance immunosuppression regimen, no clear preference can be made between azathioprine and mycophenolate, although we suggest using mycophenolate rather than azathioprine when combined with cyclosporine (Grade 2C). This suggestion is based on limited data suggesting possible greater efficacy with mycophenolate. Dosing information is provided in the table (table 1). (See 'Mycophenolate mofetil versus azathioprine' above.)

Azathioprine is metabolized by the enzyme thiopurine S-methyltransferase (TPMT). Approximately 10 percent of the population has a deficiency in this enzyme, which increases the risk of acute azathioprine-induced myelosuppression. Some transplant centers assess TPMT status (TPMT genotype and/or TPMT enzyme activity) at the time of listing for transplant or prior to initiation of the drug. All patients should undergo monitoring of blood counts and liver function while on azathioprine. Dosing information is provided in the table (table 1). (See "Overview of pharmacogenomics", section on 'Thiopurines and polymorphisms in TPMT and NUDT15' and "Thiopurines: Pretreatment testing and approach to therapeutic drug monitoring for adults with inflammatory bowel disease".)

●Mechanistic target of rapamycin (mTOR) inhibitors – The mechanistic target of rapamycin (mTOR) inhibitors, sirolimus and everolimus, are antiproliferative agents that are typically used when a patient does not tolerate the nucleotide blocking agents or has allograft rejection that is refractory to these agents. However, sirolimus and everolimus should not be used until after the bronchial anastomosis has completely healed (approximately 30 to 90 days). Dosing information is provided in the table (table 1). (See 'mTOR inhibitors' above and "Airway complications after lung transplantation", section on 'Delaying use of sirolimus'.)

●Monitoring – Ongoing monitoring of blood counts, glucose, potassium, magnesium, kidney and liver function, lipids, and drug levels is essential. The specific frequency of testing varies among centers (table 6). (See 'Monitoring and adjusting maintenance therapy' above.)

●After the first year – The level of immunosuppression is often reduced after the first year following transplantation if a patient remains stable without evidence of rejection. (See 'Monitoring and adjusting maintenance therapy' above.)

Conversely, patients who develop acute or chronic lung transplant rejection may need regimen intensification; the diagnosis and treatment of lung transplant rejection are discussed in detail separately. (See "Evaluation and treatment of acute cellular lung transplant rejection" and "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome" and "Chronic lung allograft dysfunction: Restrictive allograft syndrome".)

●Drug interactions – Many of the drugs used for maintenance immunosuppression, particularly the calcineurin and mTOR inhibitors, are metabolized by the cytochrome P450 (eg, CYP 3A4) enzyme system and/or are substrates for the P-glycoprotein efflux pump. Potential drug interactions affecting these agents, along with recommendations for alternatives, additional monitoring and/or dose adjustments are listed in the tables (table 2 and table 4). (See 'Calcineurin inhibitors' above and 'mTOR inhibitors' above.)

●Opportunistic infection – Opportunistic infection is a major side effect of immunosuppression for organ transplantation. Regimens for prophylaxis against bacterial, fungal and viral infections post-transplant are discussed separately. (See "Bacterial infections following lung transplantation", section on 'Prophylaxis' and "Bacterial infections following lung transplantation", section on 'Vaccination' and "Viral infections following lung transplantation", section on 'Summary and recommendations' and "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients" and "Fungal infections following lung transplantation", section on 'Prophylaxis'.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Pamela McShane, MD and Sangeeta Bhorade, MD, who contributed to earlier versions of this topic review.