Immunosuppression in Lung Transplantation

Changing Perspectives

Abstract

Lung transplantation is a definitive treatment option for select end-stage lung disease patients. Post lung transplantation, immunosuppression plays a significant role in a successful outcome. Rejection and infection are commonly encountered where immunosuppression plays an important role. Many immunosuppressive strategies have been designed and their protocols might vary from center to center. This review will focus on these perspectives as well as emerging perspectives during COVID times.

Introduction

Since the first successful long-term lung transplant by Toronto group in 1983, lung transplantation-related immunosuppression has undergone many exciting changes. Numerous immunosuppressive agents are now available for management after lung transplantation leading to personalized immunosuppressive therapy. It has led to better success including lower acute rejection (AR) rates and improved survival as mentioned by McDermott and Girgis.[¹] Standard maintenance therapy consists of triple-drug therapy with a calcineurin inhibitor (CNI) (cyclosporine or tacrolimus), antiproliferative agent (azathioprine [AZA], mycophenolate, sirolimus [SRL], and everolimus [EVL]), and corticosteroids (CSs) although protocols may vary center to center. Approximately 50% of lung transplant centers utilize induction therapy, with antithymocyte globulin (ATG), interleukin-2 receptor antagonists (IL2RAs) (daclizumab or basiliximab), or alemtuzumab as mentioned by Scheffert and Raza.[²]

This review will discuss these agents [Figure 1] and the literature regarding their utility in lung transplantation, as well as newer therapies and COVID-related changes in immunosuppression postlung transplantation.

Figure 1: Various immunosuppressants and their sites of action. (APC: Antigen-presenting cell, CLS: Cyclosporine, TAC: Tacrolimus, AZA: Azathioprine, MMF: Mycophenolate Mofetil, ATG: Antithymocyte globulin, SRL: Sirolimus, and EVL: Everolimus) Proposed by Dr. Unmil Shah, Dr. Vijil Rahulan, Dr. Pradeep Kumar, Dr. Prabhat Dutta, Dr. Sandeep Attawar)

Materials and Methods

A literature search was conducted on PubMed for all studies matching the eligibility criteria between till July 2020. The search included terms like “Lung Transplantation”, “Immunosuppression”, “Rejection”, “Induction”, “Maintenance”. Randomised Control Trials (RCT) were primary focus, however other review articles, studies regarding immunosuppression in lung transplantation were also eligible. Bibliographies of included studies were also reviewed. Consensus for studies included for review was achieved by discussion between authors based on predetermined eligibility criteria which included RCTs, review articles, uncontrolled studies, etc on immunosuppression in lung transplantation.

Induction Immunosuppression

Induction therapy is an immunosuppressant therapy given perioperatively to reduce the risk of AR, primarily targeting T-lymphocytes, which are considered the effector cells in cell-mediated rejection.[²] Induction agents can be divided into two groups: A nonlymphocyte-depleting agent: basiliximab (Simulect®) and two T-cell-depleting agents: rabbit ATG (rATG, Thymoglobulin®) and alemtuzumab (Campath®).[¹]

Basiliximab is a monoclonal antibody directed against CD25, the interleukin-2 receptor alpha chain of activated T-cells. rATG is made by immunizing rabbits with human thymocytes with resulting rabbit immune globulins against human T-cells. It reduces the number of circulating T-lymphocytes, which alters T-cell activation and cytotoxic function and affects cell-mediated and humoral immunity. Alemtuzumab is a humanized monoclonal antibody targeting CD52 which is located on T- and B-cells, NK cells, and to lesser degree monocytes and macrophages. The resultant antibody-dependent cellular cytotoxicity results in profound depletion of T-cells and to a lesser degree B-cells and monocytes as reviewed by Dermott and Girgis.[¹]

As per the 2019 International Society for Heart and Lung Transplantation (ISHLT) Registry Report by Chambers et al., the percentage of recipients receiving induction therapy is on rise with over 80% of adult lung transplant recipients transplanted in 2017 received some form of induction, up from 76% in 2016. Earlier trends in choice of induction therapy have been sustained, with increase in the recipients receiving an IL2RA and decline in the recipients receiving antilymphocyte or ATG or alemtuzumab[³] [Figure 2].

Figure 2: Induction immunosuppression for adult lung transplant recipients (transplants: January 2005–December 2017). ALG: Antilymphocyte globulin, ATG: Antithymocyte globulin, IL-2R: Interleukin-2 receptor. (ISHLT: International Society for Heart and Lung Transplantation Registry 2019)

Interleukin-2 receptor antagonists

Daclizumab and basiliximab are monoclonal antibodies directed against the IL-2 receptor of T-cells. They saturate the alpha-subunit of this receptor, thus inhibiting para-/autocrine activation and proliferation of T-cells by interleukin-2. Daclizumab is a humanized (90% human, 10% murine) monoclonal antibody that was removed from the US market in 2009 (Food and Drug Administration [FDA]), thus making basiliximab the only IL2RA available for use. Basiliximab is a chimeric (75% human, 25% murine) monoclonal antibody as documented by Scheffert and Raza.[²] Basiliximab is given as a 20-mg infusion intravenous (IV) in the operation room and then 20 mg on postoperative day 4.

In a retrospective review by Mora Cuesta et al., to compare AR with or without induction strategy in the 1^st month after lung transplantation (LTx), it was shown that out of 165 patients, 50.9% received induction with basiliximab. The group with basiliximab had a lower incidence of AR (P = 0.009). No differences were found in positive bronchoalveolar lavage (BAL) cultures (P = 0.472). No significant differences were found in the mechanical ventilation time (P = 0.052) and intensive care unit (ICU) stay (P = 0.303). The induction group had a lower length of hospital stay (P = 0.002). The authors concluded that the use of induction therapy with basiliximab in lung transplant patients reduces the incidence of AR in the 1^st month after transplant, with no differences in positive BAL cultures.[⁴]

In another study by Swarup et al., to study whether the timing of induction administration would impact the frequency and severity of AR in the 1^st year after transplantation, it was shown that the cumulative acute rejection (CAR) score for pre-implant basiliximab was 2.5 ± 2.3, significantly lower than CAR score of 4.6 ± 3.9 in the post-implant group (P = 0.025). The no-induction group had the highest CAR score at 6.3 ± 3.8 (P = 0.077 compared with the postgroup). There was no difference in freedom from bronchiolitis obliterans syndrome (BOS), survival, or invasive infections between pre- and post-implant induction groups, thus concluding that basiliximab before implant is associated with a lower CAR score over 1 year compared with induction post-implantation.[⁵]

Lymphocyte-depleting agents

ATG: ATG is made of polyclonal immunoglobulins derived from either horse or rabbit exposure to human thymocytes. The resulting polyclonal immunoglobulins are directed at multiple different human lymphocyte antigens. Immunoglobulin binding leads to complement-mediated lymphocyte cell lysis, antibody-mediated cell lysis, macrophage-mediated phagocytosis, and lymphocyte opsonization followed by removal through the reticuloendothelial system as described by Benvenuto et al.[⁶] Acute cytokine storm in response to ATG infusion should always be kept in mind. Patients may develop noncardiogenic pulmonary edema, chest pain, and shortness of breath. Milder syndromes reported are serum sickness-like illness with diffuse rash, fever, pruritus, myalgia, and arthralgia. Serum sickness may occur days to weeks after infusion. Premedication with acetaminophen, antihistamines, and CSs is usually required to minimize these reactions.

In the review by Scheffert and Raza, the authors have reviewed studies comparing IL2RAs and ATG;[²] one study indicated that IL2RAs are associated with reduced rates of AR and BOS, as well as better survival; three studies showed lesser AR and BOS and better survival with ATG, while still another showed no difference. Another study that retrospectively analyzed 3970 adult lung transplant recipients showed that 4-year graft survival in those who received induction with an IL2RA, ATG, or no induction was 64%, 60%, and 57% (P = 0.0067), respectively.

Alemtuzumab

Alemtuzumab is a monoclonal antibody directed against the cell surface marker CD52. CD52 is expressed on the surface of B-cells, T-cells, monocytes, macrophages, and NK cells. Alemtuzumab binds to this cell surface protein leading to complement-mediated cytolysis, antibody-mediated cytotoxicity, and programmed cell death. Alemtuzumab is administered as 30 mg IV before reperfusion or immediately following transplantation. Alemtuzumab has a 12-day half-life. Cell function is impaired significantly longer with monocyte, B-cell, and T-cell recovery at 3, 6, and 12 months, respectively, as reviewed by Benvenuto et al.[⁶] Considering the prolonged lymphopenia associated with alemtuzumab therapy, significant concern regarding risk of infection and posttransplant lymphoproliferative disease should be kept in mind.

In a retrospective cohort study by Whited et al., between alemtuzumab and basiliximab with 44 patients in the basiliximab group and 45 patients in the alemtuzumab group, it was shown that at 6 months, the average biopsy score was significantly lower in the alemtuzumab group than the basiliximab group (0.12 ± 0.29 vs. 0.74 ± 0.67, respectively; P < 0.0001).[⁷] Difference between infectious outcomes between the two groups was not statistically significant. Mortality at 6 months was not significantly different between the basiliximab and alemtuzumab groups, with an overall survival at 6 months of 90% in each group (log-rank P = 0.9819). Alemtuzumab provided superior outcomes in regard to average biopsy score and lower incidence of Grade 2 or higher rejection at 6 months.

In another study by Furuya et al. to study the role of alemtuzumab and basiliximab induction on patient survival and time to BOS in lung transplantation recipients, it was demonstrated that median survival was longer for alemtuzumab and basiliximab recipients compared with patients who received no induction (2321 vs. 2352 vs. 1967 days, P = 0.001).[⁸] Alemtuzumab (hazard ratio: 0.80, 95% confidence interval [CI]: 0.67–0.95, P = 0.009) and basiliximab induction (0.88, 0.80–0.98, P = 0.015) were independently associated with survival on multivariate analysis. At 5 years, alemtuzumab recipients had a lower incidence of BOS (22.7% vs. 55.4 vs. 55.9%), and its use was independently associated with lower risk of developing BOS on multivariate analysis. While both induction therapies were associated with improved survival, patients who received alemtuzumab had greater median freedom from BOS. Other some important trials [Table 1].

Table 1: Some other important trials

Even though the use of induction immunosuppression is not yet practiced at all centers in lung transplantation, the use is becoming common. The evidence suggests that it is associated with lesser rates of acute cellular rejection (ACR) and better overall survival. The possibility of increased infectious and malignant complications associated with the use of some induction therapies should be kept in mind.[⁶]

Maintenance Immunosuppression

The aim of maintenance immunosuppression after lung transplantation is to prevent acute and chronic rejection (CR). This is balanced by the need to prevent adverse side effects, infectious complications, and the risk of malignancy from the immunosuppressants. Standard maintenance immunosuppressive regimens consist of triple-drug therapy with a CNI, antiproliferative agent, and CSs. According to the 2019 ISHLT registry database report, after induction, the proportion of patients receiving tacrolimus plus mycophenolate mofetil (MMF) or mycophenolic acid has plateaued in the past few years.[³] On average, 62% of patients transplanted between 2005 and June 2018 were receiving tacrolimus, MMF or mycophenolic acid, and prednisone at 1-year posttransplant; however, the proportion in most recent years is higher. The use of cyclosporine and AZA continues to gradually decline.

The use of cyclosporine and AZA has seen a steady decline in the last decade while the introduction of mammalian target of rapamycin (mTOR) inhibitors and a co-simulation blocker has emerged to aid in maintenance immunosuppression for those who do not tolerate a conventional regimen as per ISHLT registry data 2018[⁹] [Figure 3].

Figure 3: Maintenance immunosuppression as a percentage for all adult lung transplantation at 1-year follow-up reported to the International Society of Heart and Lung Transplantation registry database (Registry 2018)

Calcineurin inhibitors

Since FDA approval of cyclosporine in 1983 and then tacrolimus in 1997, CNIs are an important part of maintenance immunosuppression. Cyclosporine binds to intracellular cyclophilin in T-lymphocytes and tacrolimus binds to intracellular FKBP-12, both of which form a complex that inhibits the phosphatase activity of calcineurin, preventing transcription of cytokines such as IL-2, leading to decreased activation and proliferation of T-lymphocytes. Tacrolimus is used commonly in maintenance immunosuppression, as most studies have shown an improvement in incidence of AR and long-term outcomes including a lesser risk for chronic lung allograft dysfunction (CLAD) as compared to cyclosporine as reviewed by Chung and Dilling.[¹⁰]

Tacrolimus is considerably more potent than cyclosporine and has an oral bioavailability of around 20%–25% as described by Benvenuto et al.[⁶]

In a randomized control trial by Treede et al. between tacrolimus and cyclosporine, it was demonstrated that cumulative incidence of BOS Grade ≥1 at 3 years was 11.6% (tacrolimus) versus 21.3% (cyclosporine) (cumulative incidence curves, P = 0.037 by Gray's test, pooled over strata).[¹¹] Three-year cumulative incidence of AR was 67.4% (tacrolimus) versus 74.9% (cyclosporine) (P = 0.118 by Gray's test). One- and 3-year survival rates were 84.6% and 78.7% (tacrolimus) versus 88.6% and 82.8% (cyclosporine) (P = 0.382 by log-rank test). Cumulative infection rates were similar (P = 0.91), but there was a trend toward new-onset renal failure with tacrolimus (P = 0.09). Compared with cyclosporine, de novo tacrolimus use was found to be associated with a significantly reduced risk for BOS Grade ≥1 at 3 years despite a similar rate of AR.

Tacrolimus has shown superiority over cyclosporine in a limited number of randomized studies regarding CR incidence, CR-free survival, lymphocytic bronchiolitis, and arterial hypertension without an effect on AR or survival. Tacrolimus may be associated with a higher incidence of posttransplant diabetes as elaborated by van Herck et al.[¹²]

Sublingual tacrolimus is another short-term alternative to oral and IV tacrolimus with favorable outcomes. Sublingual administration avoids first-pass metabolism or impaired gastric emptying as described by Ivulich et al.[¹³]

Therapeutic drug monitoring

Tacrolimus is characterized by a narrow therapeutic window, and TDM is mandatory to minimize the risk of rejection and toxicity. Tacrolimus dosing is routinely based on trough concentrations (C0). The relationship between single-time concentration points and AUC0-12 was investigated in the first 3 months post-LTx, with tacrolimus C0 shown to be an accurate indicator of drug exposure.[¹³]

Antimetabolites

AZA and MMF are antimetabolites which inhibit the purine and/or pyrimidine synthesis and thus block the de novo pathway of nucleotide synthesis in cells. Another pathway, a salvage pathway, also provides nucleotide synthesis in most cells. As lymphocytes lack a salvage pathway, AZA and MMF specifically exert their antiproliferative effect on these cells as described by van Herck et al.[¹²]

In a randomized control trial by McNeil et al. between AZA and MMF, it was shown that the incidence of AR and the time to first rejection event at 1 and 3 years did not differ between groups (54.1% vs. 53.8% and 56.6% vs. 60.3% for MMF and AZA, respectively). Survival at 1 year was better in patients receiving MMF (88 vs. 80%, P = 0.07). At year 3, there was no difference in survival or in the incidence, severity, or time to acquisition of BOS between the two groups. No differences were seen in the incidence of AR or BOS in lung transplant recipients treated with MMF or AZA.[¹⁴]

MMF significantly reduced graft loss due to CR in comparison to AZA in LTx. However, two randomized trials could not demonstrate a difference in AR rates, CR-free and overall survival between MMF or AZA maintenance treatment. Thus, despite the increasing use of MMF, there is limited evidence of superiority of MMF over AZA in LTx, as reviewed by van Herck et al.[¹²]

Corticosteroids

CSs suppress multiple inflammatory genes leading to a decrease in T-cell proliferation, decrease in macrophage activation, inhibition of cytokine production, and altered lymphocyte migration as mentioned by Chung and Dilling.[¹⁰]

Prednisolone is the common glucocorticoid used after lung transplant; usually, after an induction dose, it is reduced to 0.5 mg/kg/day in the immediate posttransplant period followed by a reduction over the next several months to a dose of 5–10 mg for maintenance treatment as elaborated by Benvenuto et al.[⁶]

Initial doses range from 500 to 1000 mg given intraoperatively and are gradually tapered over weeks to months to 5–10 mg per day for maintenance. Using corticosteroids is associated with side effects such as hypertension, weight gain, hyperlipidemia, hyperglycemia and diabetes mellitus, osteoporosis and increased risk of fractures, increased risk of cataracts, poor wound healing, psychiatric disturbances, and infectious complications as described by Scheffert and Raza.[²] The authors further mention that complete steroid withdrawal should be avoided at the present time, owing to a significant risk of allograft dysfunction. Doses should be lowered as quickly and as safely as possible and maintain the lowest possible doses with the aim of stable and optimal lung function and reduce drug-related side effects.

Mammalian target of rapamycin inhibitors

Sirolimus and EVL are mTOR inhibitors that act by binding FKBP12 to form a drug-protein complex like tacrolimus. They block the mTOR, stopping DNA synthesis and subsequently the proliferation of T- and B-cells. Target trough levels for sirolimus and EVL range from 5 to 15 and 3–8 ng/mL, respectively. The adverse effects are myelosuppression, diarrhea, mouth ulcers, hyperlipidemia, refractory edema, and impaired wound healing which can affect airway anastomosis as elaborated by Benvenuto et al.[⁶]

Two multicenter randomized trials did not show a difference in CR incidence, CR-free survival, and overall survival between EVL and AZA, or EVL and de novo enteric-coated mycophenolate sodium as part of the triple-immunosuppression regimen as reviewed by van Herck et al.[¹²] The authors also reviewed that sirolimus was associated with important side effects such as venous thromboembolism and impaired bronchial anastomosis healing. Nephrotoxicity is a known side effect of CNIs. Adding an mTOR to reduce CNI exposure may help renal function without significant change in AR and forced expiratory volume in 1 s (FEV1). mTOR inhibitors seem to be associated with a lesser incidence of CMV infections in solid-organ transplant patients as reviewed by van Herck et al.[¹²]

The risk of impaired wound healing associated with mTOR inhibitor use is significant in lung transplant recipients. SRL use in the immediate postoperative period has been associated with the complication of poor airway wound healing. Two studies examining SRL use after lung transplant were terminated early due to severe bronchial dehiscence with experimental studies demonstrating similar concerns with EVL. Confirmation of complete bronchial anastomosis healing is important before mTOR inhibitors can be used as suggested by Fine and Kushwaha.[¹⁵]

Both SRL and EVL have been used as an alternative to antimetabolites, to decrease CNI doses and their nephrotoxic effects, prevention of malignancy in those at high-risk, and for the prevention and treatment of CLAD. The data on improvement of renal function are equivocal as the early benefits provided by mTOR inhibitors may not be available long term in lung transplantation as reviewed by Chung and Dilling.[¹⁰]

In a randomized control trial by Gottlieb et al., EVL-based quadruple therapy versus standard triple therapy early after lung transplantation, patients received in the quadruple low CNI regimen, EVL (target trough level 3–5 ng/mL) with reduced CNI (tacrolimus 3–5 ng/mL or cyclosporine 25–75 ng/mL), and a cell cycle inhibitor plus prednisone. In the standard triple CNI regimen, patients received tacrolimus (target trough level >5 ng/mL) or cyclosporine (>100 ng/mL) and a cell cycle inhibitor plus prednisone. The primary endpoint (estimated glomerular filtration rate [eGFR] after 12 months) showed the superiority of the quadruple low CNI regimen: 64.5 mL/min versus 54.6 mL/min for the standard triple group (least-squares mean, analysis of covariance; P < 0.001). Biopsy-proven AR, CLAD, death, and safety endpoints were similar between both groups. Quadruple low CNI immunosuppression early after lung transplantation was demonstrated to be efficacious and safe[¹⁶] Other some important trials [Table 2].

Table 2: Some other important trials

Co-stimulation blocker

Belatacept inhibits T-cell proliferation and cytokine production by blocking CD28-mediated co-stimulation of T-lymphocytes as elaborated by Chung and Dilling.[¹⁰]

In a retrospective case series of 11 lung transplant patients who underwent conversion from a CNI-based to a belatacept-based immunosuppressive regimen (ISR) due to intolerance, by Iasella et al., it was demonstrated that belatacept-based ISR appears to produce reasonable results in recipients who fail CNI-based ISR. Mean eGFR was significantly higher post belatacept (32.53 vs. 45.26, P = 0.04). Mean incidence of infections (24.4% vs. 16.0%, P = 0.55) and mean arterial pressure (97.5 vs. 92.1 P = 0.38) were not different. Progression of CLAD occurred in two patients. At the end of follow-up, 7 of 11 patients were alive. Reason for change to belatacept was for thrombotic thrombocytopenic purpura (4), posterior reversible encephalopathy syndrome (3), recurrent ACR (2), CLAD (1), and renal sparing (1).[¹⁷]

In a study by Timofte et al., using belatacept for lung transplant recipients with severe renal insufficiency to reduce nephrotoxic immunosuppressive exposure in 8 patients because of acute or chronic renal insufficiency (median) GFR 24 (interquartile range: 18–26), it was shown that GFR remained stable in two patients and increased in five patients. One patient with established renal and respiratory failure received only the induction dose of belatacept and died 4 months later of respiratory and multisystem organ failure. CNI or SRL exposure was safely withheld or reduced without moderate or severe AR during ongoing belatacept in the other seven patients. FEV1 remained stable over the 6-month study interval. Belatacept use appears to permit a safe transient reduction in conventional immunosuppressive therapy and was associated with stable or improved renal function.[¹⁸]

Rejection salvage regimens

Rejections encountered postlung transplant commonly are either ACR or antibody-mediated rejection (AMR). AMR treatment strategies involve disrupting the production of or depleting the amount of circulating antibodies. IV methylprednisolone, intravenous immunoglobulin (IVIG), plasmapheresis, and rituximab are all strategies reported in the literature. Plasmapheresis removes circulating antibodies and donor-specific antibodies (DSA) that could target the allograft. IVIG has a combination of effects resulting in apoptosis of B-cells and inhibition of the antibody-mediated complement pathway. Rituximab is a monoclonal anti-CD20 antibody specific for B-cells that cause apoptosis and ultimately B-cell depletion. Bortezomib (BTZ) and carfilzomib (CFZ) are proteasome inhibitors that cause plasma cell apoptosis as elaborated by Benvenuto et al.[⁶]

In a study by Vacha et al., using a standardized protocol of plasma exchange, steroids, BTZ, rituximab, and IV immune globulin to treat AMR, they showed the clearance of DSAs and preserved lung function in a minority of lung transplant recipients with suspected AMR surviving to 6 months after therapy. Of the 16 patients, 11 survived 6 months. Three of those 11 patients (27%) cleared all DSAs within 6 months of the protocol. Four of the 11 patients (36%) had preserved allograft function at 6 months. Twelve-month patient survival was 56%.[¹⁹]

Treatment protocols vary from center to center, but options are limited to high-dose or “pulse” CS (e.g., methylprednisolone 10–15 mg/kg IV daily × 3–5 days), particularly for initial treatment or minimal-mild grade ACR, ATG (1.5 mg/kg IV daily × 3–5 days) or alemtuzumab (30 mg IV once) for moderate-severe grade ACR or steroid-resistant/steroid-refractory ACR. Options available for the treatment of AMR include plasmapheresis (5–6 cycles), IVIG (1–2 g/kg over 3–6 days), rituximab (375 mg/m² IV weekly × 4 doses or 1,000 mg IV every 2 weeks × 2 doses), and/or BTZ (1–1.3 mg/m² every 72 h × 4 doses).[²]

Proteasome inhibitors

BTZ is a monoclonal antibody directed at the 26S proteasome. Binding to active site of 26S leads to plasma cell apoptosis. Typical dosing of BTZ involves 4 doses of 1.3 mg/m². The use of BTZ in AMR has shown to be effective in case reports as reviewed by Kulkarni et al.[²⁰]

Carfilzomib

CFZ is a second-generation proteasome inhibitor. A study using CFZ in lung transplant examined the loss of DSA fixing ability in vitro after CFZ therapy with plasmapheresis and IVIG. It helped in removal of C1q-fixing DSA and depletion of circulating immunodominant DSA as being associated with the return of graft function as mentioned in review by Chandrashekaran et al.[²¹]

Eculizumab

The eculizumab (ECU) is a monoclonal antibody to C5. Case reports using ECU as part of a multipronged therapy for AMR have shown depletion of DSA and improvement in allograft function, as reviewed by Bery and Hachem[²²] [Table 2].

Newer modalities at the horizon

Inhaled cyclosporine

There has been interest in topical delivery of cyclosporine in allograft to increase its concentration in it. In a single-center, randomized, double-blind, placebo-controlled trial of inhaled CSA, there was no improvement in the rate of ACR, but survival and CR-free survival did improve as documented by Iacono et al.[²³]

Extended-release tacrolimus

Two studies have been performed using extended-release tacrolimus in lung transplantation as reviewed by Patel et al.[²⁴] The first study demonstrated that converting patients from tacrolimus-BID to extended-release tacrolimus on a 1:1 basis provides identical drug exposure when analyzed by the AUC0-24 in the lung transplant population. The second study showed that in cystic fibrosis patients status post (s/p) lung transplant, extended-release tacrolimus is a possible alternative, but on average, they need a 28% increase in dose and the range of the increase can be up to 67%.

Tocilizumab

Tocilizumab has been tried as a part of combination therapy to treat CLAD in lung transplant patients. In a study by Ross et al., the authors showed that using tocilizumab (4–8 mg/kg/month) as a part of combination (rabbit ATG, rituximab, and IVIG + TCZ), combination therapies for CLAD can stabilize spirometry decline without apparent significant adverse effects. This adds tocilizumab in the armamentarium to treat a difficult condition like CLAD.[²⁵]

Pediatric Liver Transplantation

In the review by Ivulich et al., its documented that survival in children after LTx is similar to that reported in adults, with a median survival of 5.4 versus 5.9 years.[¹³] The long-term success is limited by CLAD, occurring in 38% of patients at 5 years post-LTx. Immunosuppressive regimens are similar to those utilized in adults, with tacrolimus being prescribed in 97% and mycophenolate in 82% of patients. More than 90% of children are on a corticosteroid at 5 years post-LTx. Medication adherence remains a major barrier to the long-term success. Pediatric nonadherence is as high as 80% with adolescent patients.

Pregnancy

In a retrospective analysis by Thakrar et al. of 19 recipients with pregnancy posttransplant, some interesting facts were elaborated. The mean age was 31.4 years (range, 22–39 years), and the mean time from transplant was 76.2 months (range, 26–139 months).[²⁶] Recommendations given by the authors were (a) pre-pregnancy, at least 2 years posttransplant required before planning pregnancy, immunosuppression should be AZA, CNI, and prednisone. Tacrolimus, cyclosporine, and prednisolone are all considered Class C medications, and therefore, their use is continued through pregnancy. MMF is generally stopped. (b) Pregnancy: Frequent checks of CNI level and renal function are recommended because of physiological changes during pregnancy. (c) Post-pregnancy: Infectious complications are common and need to watch out for rejections and BOS. Thus, multidisciplinary approach is the key to successful pregnancy posttransplant.

Hiv

In the short case series of HIV-seropositive recipients, Kern et al. have illustrated few salient points. First, lung transplantation is feasible in HIV-seropositive recipients in the setting of controlled HIV infection.[²⁷] Second, the authors observed a low incidence of infections with nearly no detectable viremia. Drug-to-drug interactions were manageable. Efavirenz increases the metabolism of CNIs, but its own metabolism is decreased by voriconazole. Using voriconazole for aspergillosis prophylaxis poses challenges in efavirenz dosing, necessitating a 50% dose reduction with a concomitant >100% increase in the prophylactic dose of voriconazole. Standard tacrolimus trough targets and the duration of fungal prophylaxis were not adjusted in the study. Using ritonavir required a dramatic reduction in tacrolimus dosing. The use of protease inhibitors, especially ritonavir, requires monitoring for drug toxicities. The authors also concluded that acute graft rejection may be more common in such patients.

Hepatitis C Virus

The highly potent direct-acting antivirals are useful for patient management of hepatitis C virus (HCV). Sofosbuvir-based regimens can be started before or after lung transplant, with less side effects and limited drug–drug interactions and a cure rate of at least 90%, with no progression of liver fibrosis as mentioned by review by Ivulich et al.[¹³] In a review of 27 HCV-positive recipients by Doucette et al., it was shown that the 1-, 3-, and 5-year survivals were similar in HCV RNA-positive versus HCV RNA-negative recipients at 93%, 77%, and 77% versus 86%, 75%, and 66% (P = 0.93), respectively. Long-term follow-up in eight patients demonstrated no significant progression of fibrosis. Thus, HCV did not affect lung transplant outcomes.[²⁸]

Novel Researches

Torque teno viruses (TTVs) are ubiquitous DNA viruses in humans, currently classified into the family Circoviridae, genus Anellovirus. They have been seen as a promising surrogate marker of the immune system in immune-compromised patients but not found to be causative for any disease as reviewed by Frye et al.[²⁹] In their study of 34 LT recipients, it was shown an increase of TTV-DNA after lung transplantation reaching a steady state after 3–4 months. They showed that higher TTV-DNA levels reflect more intense immunosuppression, whereas the TTV-DNA kinetic (i.e., decrease of TTV-DNA levels) indicates rejection. Thus, further studies on TTV DNA kinetics might be useful to establish its role as a monitoring tool for immunosuppression.

The ImmuKnow immune cell function assay (Cylex, Inc., Columbia, MD, USA) measures the amount of adenosine triphosphate (ATP) produced by helper CD4+ cells after stimulation with phytohemagglutinin-L, a T-cell mitogen, in vitro. It is of potential interest as an objective measure of overall immune function in solid organ transplant recipients.[³⁰] In a study by Shino et al., it was shown that the mean ATP level was 431 ± 189 ng/ml for the rejection group versus 377 ± 187 ng/ml for the healthy group (P = 0.10). The mean ATP level was 323 ± 169 ng/ml for the infection group versus 377 ± 187 ng/ml for the healthy group (P = 0.03). A recipient with an ATP level >525 ng/ml was 2.1 times more likely to have ACR (95% CI: 1.1–3.8). A recipient with an ATP level <225 ng/ml was 1.9 times more likely to have respiratory infection (95% CI, 1.1–3.3). Thus, ImmuKnow assay might be useful to assess the immune system and might be helpful in predicting risk of infection posttransplant but further studies required.

In a study by Piloni et al., the ImmuKnow assay levels were significantly lower in infected lung transplant recipients compared with noninfected recipients and in RAS patients.[³¹]

Immunosuppression in COVID-19 Posttransplant

Since COVID-19 (novel Coronavirus disease) is a newer disease, guidelines regarding changes in immunosuppression are not yet available. However, by reviewing the limited literature available, it has been shown that reducing immunosuppression in COVID infection helps in better outcome. Either reducing CNI doses, reducing doses/stopping antimetabolites, and keeping low-dose steroids are the various options available in managing immunosuppression during COVID infection post-SOT transplant which has to decided case to case as elaborated by Zhang et al.[³²] Correlating with cyclic threshold values might help in making a clinical decision as demonstrated in a report by Aigner et al.[³³]

Conclusion

Planning immunosuppression in lung transplant determines success short term as well as long term. Individualizing regimens helps in minimizing side effects and better adherence. Therapeutic drug monitoring is important and should be standardized and validated for other drugs in the regimen. Newer drugs, newer routes of administration, and newer methods to check levels of immunosuppression would go a long way in improving success post lung transplant.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.