Bronchiolitis Obliterans Syndrome Complicating Lung or Heart-Lung Transplantation

John A. Belperio, MD; Kathleen Lake, PharmD; Henry Tazelaar, MD; Michael P. Keane, MD; Robert M. Strieter, MD; Joseph P. Lynch, III, MD

Disclosures

Semin Respir Crit Care Med. 2003;24(5) 

In This Article

Current Therapy for BOS

Despite advances in pharmacological immunosuppressive therapy, prevention and treatment of chronic lung allograft rejection remain disappointing. Based on the complex interaction between the occurrence of AR and the subsequent development of BOS,[5,16,25,79] a logical strategy to prevent BOS has been to prevent or treat AR. Augmentation of immunosuppressive therapy is routinely administered in patients with BOS or OB[218,219] but is of unproven value.[18,20,220] Furthermore, overly aggressive immunosuppressive therapy heightens the risk for opportunistic infections, malignancy, and other complications.[221]

The standard approach to treat BOS is to intensify immunosuppression. Intravenous pulse methylprednisolone (e.g., 1000 mg daily for 3 days) is often administered, and treatment response is monitored within 3 to 6 weeks. Blood levels of immunosuppressive agents [e.g., calcineurin inhibitors, mycophenolate mofetil (MMF), etc.] are measured to assure therapeutic concentrations and patient compliance. In many centers, maintenance therapy is changed [e.g., tacrolimus (TRL) replaces cyclosporin A (CsA) or MMF replaces azathioprine (AZA)]. When patients continue to deteriorate, cytolytic agents [e.g., OKT3, antithymocyte globulin (ATG)], or additional therapeutic modalities [e.g., methotrexate (MTX), cyclophosphamide, or photopheresis] are often added.[27,222,223] These various strategies are expensive, have potential morbidity, and are of unproven benefit. Although anecdotal "responses" have been cited, this often reflects slowing in the rate of decline in lung function; actual improvement has rarely been documented. "Stabilization" of lung function is often construed as a response to therapy, yet may simply represent the natural course of BOS in some patients. The rate of loss of lung function is not linear, and the rate of deterioration in FEV1 may decline as airflow obstruction worsens. Interpretation of published studies is clouded by small sample sizes, brief duration of follow-up, heterogeneous patient populations, concomitant use of other immunomodulatory or immunosuppressive agents, and lack of suitable control groups.

Augmentation of immunosuppression is usually efficacious in treating acute allograft rejection within the first 3 to 6 months following LT, but is rarely beneficial for episodes of AR occurring at later time points.[224] In one retrospective study, 72 episodes of AR > 6 months posttransplant in 45 LTRs were treated with augmented systemic steroids.[224] FEV1 improved (> 10% increase) in only 14 patients (19%); FEV1 deteriorated further (> 10% decline) in 32 (44%); in the remaining patients, FEV1 changed by < 10% (in either direction). Further, spirometric evidence for BOS developed within 3 months in 20 of 47 patients (43%). Data regarding treatment for OB or BOS are limited to small, nonrandomized series and anecdotal reports. There are no data substantiating benefit with any form of therapy for patients with established OB or BOS. In the following sections, we examine various therapeutic modalities used to treat or prevent OB or BOS.

Tacrolimus

TRL (formerly FK506) was approved in 1994 and has been used as an alternative agent for CsA in solid organ transplant recipients,[225,226] Both TRL and CsA are calcineurin inhibitors, thereby blocking lymphokine production from helper and cytotoxic T cells.[226] Historically, immunosuppressive therapy for LTR included combination therapy with CsA, AZA, and corticosteroids (CS) (with or without induction cytolytic therapy). Within the past few years, TRL has become the preferred agent (in place of CsA) for many solid organ transplant recipients. Multicenter trials in renal and liver transplant recipients showed that TRL was superior to CsA in preventing AR and has an acceptable safety profile.[227,228,229] Four trials (three randomized; one nonrandomized) compared TRL- and CsA-based protocols in cardiac transplant recipients.[230,231,232,233] The incidence of AR during the first year was similar with both regimens; side effects (e.g., hyperlipidemia; hypertension) were less frequent with TRL. TRL has also been efficacious in CS-refractory rejection in renal,[234] liver,[235] and cardiac[236] allograft recipients.

Data evaluating TRL in LTRs are limited to two prospective trials and several nonrandomized studies (discussed following here). In a retrospective review, 30 LTRs treated with TRL, AZA, and prednisone-based immunosuppression were compared with a historical cohort receiving CsA, AZA, prednisone, and rabbit antithymocyte globulin (RATG).[237] An additional 12 patients received TRL, MMF, and prednisone. One- and 3-year actuarial survival rates were superior in the TRL + AZA cohort (93% and 71%, respectively) compared with the CsA cohort (71% and 51%, p = 0.04). The TRL + MMF group was not included in this analysis due to comparatively brief follow-up. The number of AR episodes per 100 patient days was lower in the TRL + AZA group (0.63) compared with CsA (1.50), p = 0.045. The incidence of CS-resistant AR per 100 patient days was also lower in the TRL + AZA group compared with CsA (0.03 vs 0.2, p < 0.01).

Two open-label randomized trials compared TRL with CsA in LTRs.[238,239] Keenan et al randomized 133 single or bilateral LTRs to either CsA- or TRL-based regimens.[238] One- and 2-year survival rates were similar with TRL (83% and 76%) and CsA (71% and 66%), respectively. The incidence of AR trended lower in the TRL group (0.85 vs 1.09 with CsA) (p = 0.07) Importantly, fewer patients in the TRL group developed OB (22%) compared with CSA (36%) (p = 0.025). The second prospective trial randomized 50 patients to either TRL or CsA in combination with MMF and prednisone.[239] Survival rates at 6 and 12 months were similar. However, there were fewer treated AR episodes per 100 patient days in the TRL-cohort (0.225) compared with CsA (0.426) (p < 0.05).[239] A subsequent long-term follow-up of 110 patients enrolled in that protocol was recently published in abstract form; 3-year survival rates with TRL (68%) and. CsA (57%) were similar.[240] There was a trend for more late rejections in the CsA group (24%) versus TRL (4%) (p = 0.07). Most importantly, the incidence of BOS was higher in the CsA group (41%) compared with TRL (10%) (p < 0.01). A large, international, multicenter trial comparing TRL versus CsA in combination with MMF and prednisone in 250 LTRs is under way. Interim analysis of the first 110 patients was presented at the 2003 IHSLT Annual Meeting in Vienna.[241]

TRL has been used extensively as rescue therapy for CS-resistant rejection in LTRs, with apparent "stabilization" of lung function, but data are limited to nonrandomized trials[242,243,244,245,246,247] Data are promising, but not definitive. A seminal study treated 10 single LTRs with CS-refractory BOS refractory with TRL; CsA and AZA were discontinued.[248] Although improvement was not noted, FEV1 "stabilized" following conversion to TRL. The Δ FEV1/month was -0.069/month with CSA as compared with +0.03/month with TRL (a statistically significant improvement with TRL). In another retrospective study, 20 LT recipients with refractory AR were switched from CsA to TRL.[249] Compared with CsA-based immunosuppression, TRL was associated with significant declines in mean number of episodes of AR per patient (3.0 to 0.85), incidence of AR per 100 patient-days (1.9 to 0.4), average histological grade of AR (1.9 to 0.4), and need for methoprednisolone pulses (1.9 to 0.3).[249] A recent trial evaluated 7 LFTs who were switched from CsA to TRL as soon as BOS stage I (i.e., ≥ fall in FEV1) was diagnosed.[250] No other immunosuppressive augmentation occurred. Mean FEV1 improved from 1.57 L to 2.27 L (+45%) at 6 months (p < 0.05) and to 2.05 L (+ 31%) at 12 months (p < 0.05).[250] A recent retrospective study examined the effect of substituting TRL for CsA in 32 patients with BOS.[247] Rates of decline in FEV1 and FEF25-75 were lower following conversion to TRL. Actuarial survival did not differ between the two groups (p = 0.86). Several additional studies reported apparent favorable responses in patients with BOS or OB following conversion from CsA- to TRL-based immunosuppression.[251,252,253,254,255,256] Most studies noted a decline in the rate of decrease of FEV1; improvement was rarely observed. Analysis of these various studies is clouded by differing criteria for switching, concomitant therapies, heterogeneous patient populations, and limited duration of follow-up. Although we routinely switch from CsA to TRL in LTRs with refractory rejection (acute or chronic), randomized, controlled, multicenter studies are required to establish unequivocal benefit.

Mycophenolate Mofetil

MMF, which inhibits T and B cell proliferation by blocking the enzyme inosine monophosphate dehydrogenase,[226] is superior to AZA in reducing AR episodes among renal[257,258] and cardiac[259] allograft recipients. Studies utilizing MMF in LTRs are conflicting. In three nonrandomized trials in LTRs, MMF as primary therapy (together with CsA and prednisone) was superior to AZA (utilizing historical controls).[260,261,262] Each of these studies, which included a total of 49 patients receiving MMF, found lower rates of AR in the MMF cohorts. No survival advantage was documented. A large, single-center retrospective study of 303 LTRs compared the risk of developing ≥ stage 2 BOS in 105 patients receiving MMF as part of immunosuppression immediately posttransplant compared with 108 patients who never received MMF.[263] Those receiving MMF were half as likely to develop BOS 2 (odds ratio 0.51) as compared with non-MMF patients (95% CI 0.27, 0.99; p = 0.049). Survival was similar in the two groups.

In contrast to these favorable results, two recent prospective trials evaluating MMF in LTRs found no benefit when compared with AZA-based immunosuppression.[218,264] A two-center, randomized, prospective U.S. trial compared the efficacy of MMF 2 g/day versus AZA 2 mg/kg/day in the prevention of AR in 81 LTRs.[264] Preliminary results at 6 months showed a similar incidence of biopsy-proven grade 2 or greater AR (63% with MMF, 58% with AZA, p = 0.82). Six-month survival rates in the MMF and AZA groups were similar (86% and 82%, respectively; p = 0.57). A large, prospective, open-label international trial evaluated the incidence of BOS at 3 years among 317 LT recipients treated with MMF (3 g/day initially followed by 2 g/day from 3 months) or AZA (2 mg/kg/day).[218] The incidence of AR at 12 months was similar (54% in both groups); the incidence of BOS at 3 years was also similar (27% MMF, 25% AZA). Mortality rates at 3 years were 25% with MMF; 31% with AZA (p = 0.17). That study was criticized because a large number of patients withdrew prematurely (47% in the MMF cohort; 60% in the AZA cohort). The apparent lack of difference in efficacy in preventing AR between MMF and AZA in the LTRs is surprising given that significant reductions in AR incidence were noted in other solid organ transplant recipients. In three pivotal studies in renal transplant recipients, statistically significant declines in AR were observed in MMF-treated patients as compared with controls.[257,258,265] One possible explanation for these inconsistent findings is that little is known about the pharmacokinetic variability of MMF in LTRs. Pharmacokinetics of MMF in heart and renal transplant recipients have been well characterized.[266,267,268,269,270,271,272] Less data are available in LTRs.[226,273,274] Partovi et al reported wide variability in MPA concentrations at three different time intervals following LT.[274] Several investigators have suggested a correlation between MMF concentrations and the incidence of AR in heart transplant recipients[272,275,276,277,278] Because of the significant interpatient variability, therapeutic drug monitoring should be utilized to optimize MMF therapy in LTRs.[279]

Favorable results were cited in uncontrolled studies of LTRs treated with MMF for AR rescue therapy[280] or treatment of OB.[281,282] We treated 13 patients with BOS with MMF (in place of AZA); there was no significant change in FVC, FEV1, or FEF25-75 at 3, 6, or 12 months.[281] Two died of progressive OB, but it is possible that the rate of decline of lung function may have been slowed by the addition of MMF. In another study, MMF was substituted for AZA in nine LTRs with recurrent AR.[262] The linearized rate of AR declined significantly (p = 0.04) after initiation of MMF therapy. PFTs did not change. A more recent trial evaluated 16 LTRs with BOS who were switched from AZA to MMF.[282] The mean rate of decline of the FEV1 per month was significantly reduced after conversion to MMF (p < 0.05). These various studies are not convincing. Nonetheless, we continue to recommend conversion to MMF among LFTs developing recurrent or refractory rejection on AZA-based immunosuppression.

Sirolimus

Sirolimus (SRL) (rapamycin), a macrolide structurally related to TRL, inhibits the activity of mTOR, a kinase enzyme (also the target of rapamycin), leading to inhibition of T and B cell proliferation.[226,283] SRL and related compounds inhibit response of T cells to IL-2 and other cytokines, but also inhibit growth factor-induced endothelial and mesenchymal cell proliferation.[5] SRL markedly inhibits the fibroproliferative response in animal models of chronic heart,[284] kidney,[285] and lung[286,287] allograft rejection.

No clinical trials have evaluated SRL for de novo lung transplants. However, because the mechanism of action of SRL differs from calcineurin inhibitors (e.g., CsA and TRL), SRL has been used as salvage therapy for chronic, progressive lung allograft rejection.[288] In a recent, uncontrolled study, 12 LTRs with newly diagnosed or progressive BO/BOS were treated with SRL combined with a calcineurin inhibitor and prednisone.[288] As a group, mean rate of change in FEV1 or FEF25-75 did not change with SRL. However, individual patients with the most rapid declines in slopes, ΔFEV1 or ΔFEF25-75 stabilized or improved. Adverse effects were more common with SRL. A multicenter, 3-year study is currently under way to compare the safety and efficacy of the oral rapamycin derivative (RAD) to treat BOS.[289] In that study, 233 stable lung or heart-lung recipients at risk for developing BOS were randomized to receive either everolimus (RAD) 1.5 mg b.i.d. or continue on AZA 1 to 3 mg/kg/day in addition to CsA and prednisone. The major efficacy endpoints were: decline of FEV1 > 15%; graft loss or patient death (as a composite endpoint); decline in FEV1 over time; the incidence of BOS. One-year results were presented at the 2003 annual meeting of ISHLT.[289] The mean time to randomization following LT was similar between the two groups (RAD, 14.1 months; AZA, 13.3 months). At 12 months, fewer patients treated with RAD experienced a decline in FEV1 > 15% (15.8% with RAD vs 27.7% with AZA, p = 0.034). The incidence of clinically suspected or biopsy-proven AR was lower in RAD patients (10.9% vs 26.8%, p = 0.015). Other efficacy endpoints trended in favor of RAD compared with AZA (i.e., graft loss at 12 months were 1% and 5.4%, respectively (p = 0.063); incidence rates of BOS were 14.9% and 24.1%, respectively (p = 0.09); patient death 3.0 versus 3.6%. Therapy was discontinued prematurely by 12 months in 42.3% of RAD patients as compared with 31.5% in the AZA arm. Azathioprine was discontinued in 11.7% of patients because of an unsatisfactory therapeutic effect as compared with 5.4% discontinuation with RAD. Adverse effects requiring discontinuation of therapy were more common with RAD (28.8%) compared with AZA (12.6%). These studies are unconvincing regarding therapeutic advantage of RAD over conventional immunosuppressive regimens.[288,289] Additional studies are required to determine whether SRL has a role for refractory lung allograft rejection.

Cytolytic Therapy

Cytolytic agents [e.g., OKT3 antibody, antithymocyte globulin (ATG); antilymphocyte globulin (ALG)] have been tried in LTRs with acute or chronic allograft rejection, with anecdotal responses.[290,291] Published experience with these agents to treat or prevent BOS is limited. Some retrospective studies in LTRs with BOS cite "stabilization" of lung function, as defined by a decrease in the rate of decline in FEV1, but objective benefit is difficult to ascertain.

Early in solid organ transplant experience, muromonab-CD3 (Orthoclone OKT3) monoclonal antibody was used to treat CS-refractory acute renal[292,293] or cardiac[294] allograft rejection, with high success rates. In addition, OKT3 was used in some centers as initial induction therapy for LTRs.[73,295] Nonrandomized trials in LTRs with CS-recalcitrant AR cited anecdotal responses to OKT3.[296,297] In one study, 20 LTRs with 28 episodes of AR were treated with OKT3 (5 mg/kg intravenously for 7-10 days); favorable responses were cited in 19 (68%).[296] Importantly, response rates were higher (16/18) when OKT3 was administered during the first 6 months after LT as compared with three of 10 responses at later time points (p < 0.01). Ross et al retrospectively reviewed the incidence of BOS among LTRs given two different cytolytic induction regimens [i.e., OKT3 (n = 11) or Minnesota ALG (MALG) (n = 13)].[295] All patients received maintenance immunosuppression with CsA, AZA, and prednisone. The mean number of episodes of AR (> A1) were more common in patients receiving MALG compared with OKT3 (2.23 vs 1.64). At late follow-up, BOS developed in 10 of 13 patients (77%) receiving MALG and 7 of 11 (64%) patients receiving OKT3 (p = NS [not significant]). Four deaths occurred in each group; necropsy demonstrated OB in all patients. The time of onset of BOS (stage 1) was longer in the OKT3 group (p < 0.01).

Paradis et al reported five different therapies (three different cytolytics, CS, and total lymphoid irradiation) for a total of 44 courses to treat 16 LTRs with BOS.[291] Favorable responses were cited, but the efficacy of individual agents is impossible to ascertain. An early report cited "stabilization" of lung function in two of three LTRs with BOS treated with equine ATGCATGAM therapy.[39] In a sub sequent report from Australia, Snell and colleagues retrospectively reviewed the impact of equine ATGAM (administered IV for a mean of 5.3 days) plus pulse methylprednisolone in 10 LTRs with BOS.[73] Therapy for BOS was initiated at a mean of 657 days post-LT. All had previously received lymphocyte immune globulin or ATGAM as induction therapy for the first 7 to 10 days post-LT. Following treatment with ATGAM, the mean rate of decline of FEV1 fell (from 0.22 ± 0.15% predicted FEV1 per day prior to ATGAM compared with 0.036 ± 0.019% predicted per day after ATGAM (p < 0.005). This effect was sustained over a mean of 310 days. Whether this "stabilization" reflects an effect of cytolytic therapy or the natural history of the disease (BOS) cannot be ascertained. Kesten et al treated 15 LTRs and BOS with cytolytic agents (either ALG or RATG).[298] FEV1 improved in two patients (13%), did not change in five (33%), and deteriorated further in eight (53%). The largest published series retrospectively reviewed the impact of cytolytic agents in 48 LT recipients with BOS.[297] Sixty-four courses of cytolytic therapy (e.g., ALG, ATGAM, or OKT3) were administered and effect on pulmonary function was determined. Although mean FEV1 continued to decline following cytolytic therapy, the rate of decline in FEV1 fell (mean ΔFEV1 3 months prior to and 3 months after cytolytic therapy was -23.5% and -9.9%, respectively). No differences between the various cytolytic agents were observed. Again, whether the decline in mean ΔFEV1 reflects the impact of cytolytic therapy cannot be ascertained. However, the impact of cytolytic therapy appears to be marginal. Only four patients improved. Most patients progressed to higher (worse) stages of BOS and 40% died within 2 years of initiation of cytolytic therapy. Administration of these cytoloytic antibody preparations is expensive and logistically difficult and has potential severe adverse effects (e.g., cytokine release syndrome, pulmonary edema, hypotension, opportunistic infections).[296,297] Our experience with these agents for BOS has been disappointing.

IL-2 Receptor Antagonists

The addition of antagonists against the IL-2 receptor (e.g., daclizumab, basiliximab) to conventional immunosuppressive has been shown to reduce the incidence of AR in renal and heart transplant recipients.[299,300,301] However, daclizumab did not affect graft survival at 12 months. Daclizumab binds the α-subunit of the IL-2 receptor and inhibits binding of IL-2.[302,303] We are aware of only three published studies utilizing these agents among LTRs.[304,305,306] In a prospective, nonrandomized trial, rates of AR were similar with the three treatment arms (i.e., OKT3, ATG, and daclizumab).[304] The incidence of infections was lower in the daclizumab arm. The incidence of BOS was lower in the daclizumab arm but follow-up was shorter in that group. A retrospective study cited a lower incidence of ≥ grade 2 AR among LTRs receiving daclizumab (18%) compared with historical controls treated with TRL, AZA, and prednisone (48%), p < 0.04.[305] The incidence of infection was similar in the two groups. Marom et al retrospectively reviewed 86 LTRs; 43 patients received two doses of daclizumab (on days 0 and 4) in addition to conventional immunosuppression.[306] The historical control group (n = 43) received CsA, AZA, and prednisone. Rates of early reperfusion injury, pulmonary edema, and survival (at 1, 3, 6, and 12 months posttransplant) were similar between daclizumab and control groups.

Methotrexate

MTX has been used to treat recalcitrant AR in cardiac transplant recipients[307,308,309,310] and is effective as maintenance immunosuppression among renal allograft recipients.[311] Data in LTRs are limited to two uncontrolled series.[113,312] In an uncontrolled, open study, 10 LTRs with persistent or progressive BOS were treated with oral MTX (once weekly).[113] Following initiation of MTX, the rate of decline in FEV1 decreased at 6 and 12 months. Mean decline in FEV1 at 6 and 12 months after initiation of MTX was -0.04 L (-1.6%) and -0.26 L (-11.6%), respectively, compared with mean decline of 11.3 L (-41%) from 12 months prior to the start of MTX. In another study, 12 LTRs with AR were treated with MTX (once weekly orally or subcutaneously for 6 weeks).[312] AR resolved in all patients completing at least 4 weeks of MTX therapy. Ten of 12 (83%) had no further episodes of AR during a mean follow-up period of 12.5 months. However, BOS developed in five patients (42%). The incidences of histological BO and survival were similar among MTX-treated patients compared with LTRs not receiving MTX. These data suggest that MTX may be efficacious in treating AR but may have no effect in treating established BOS.

Cyclophosphamide

Cyclophosphamide (CP), an alkylating agent with potent immunosuppressive effects,[221] has rarely been used to treat refractory allograft rejection in solid organ transplant recipients. The combination of TRL and CP prolonged survival of hamster-to-rat pulmonary xenografts.[313] Among human heart transplant recipients, CP may have an additive effect in treating vascular rejection.[314] In an open-label, uncontrolled trial, seven LTRs with chronic, persistent rejection unresponsive to conventional therapy were treated with oral CP (0.5-1 mg/kg/day) in lieu of AZA.[315] Mean FEV1 at entry and at 3 and 6 months after CP was 1.63 L, 1.77 L, and 1.79 L, respectively (differences not significant). One patient died of progressive OB after 18 months of therapy whereas six were alive, with a mean FEV1 at last follow-up of 1.71 L. Cyclophosphamide is oncogenic and has myriad potential adverse effects.[221] We see little role for this agent in treating BOS.

Total Lymphoid Irradiation

Total lymphoid irradiation (TLI) has been used to treat refractory acute and chronic rejection in heart and lung transplant recipients, with anecdotal successes.[44,291,316,317,318,319,320,321,322,323,324] In one study, six heart-lung or lung transplant recipients with CS-recalcitrant AR were treated with TLI.[323] Five survived at least 1 year following TLI; two survived more than 4 years. In another study, 11 patients with chronic lung allograft rejection refactory to conventional therapies were treated with TLI.[322] Only four were able to complete all 10 treatment fractions. Seven patients failed therapy (six due to progressive pulmonary decline). Overall, six patients died. Among four "responders," FEV1 did not change at 3 months (average ΔFEV1 + 1% vs 40% decline before TLI). However, there was less need for augmented immunosuppression in the four "responders" (3.5 courses of therapy before vs 0 after). In another uncontrolled study, 12 patients were treated with TLI for OB; the rate of decline in lung function decreased following TLI, but whether this reflected the natural history of the disease is not clear.[44] These studies are inadequate to assess the efficacy (if any) of TLI for BOS.[44,322]

Extracorporeal photochemotherapy (ECP), which involves irradiating the recipient's mononuclear cells with ultraviolet light in the presence of 8-methoxy-psoralene (8-MOP), results in the specific destruction of clones of photomodulated T cells.[325,326] ECP was effective in preventing[327] and reversing acute cardiac allograft rejection.[328,329,330,331] Data in LTRs are limited to anecdotal reports and small uncontrolled series. Anecdotal responses to ECP have been cited in LTR with AR[332,333] and OB.[321,334,335] Transient improvement or stabilization was achieved in a few patients, but long-term benefit is unknown.

Aerosolized CsA has been used as rescue therapy in LTRs failing conventional immunosuppression.[251,336,337,338,339] Stabilization of PFTs has been reported[338,340] but adverse effects (e.g., sore throat, cough, wheezing, dyspnea) limit its widespread use.[226]

Inhaled anti-inflammatory CS have been used to treat LBB or OB, but benefit is unproven. In one study, 14 LTRs with isolated LBB were treated with inhaled budesonide 800 µg twice daily.[341] Following inhaled CS, both eNO and FEV1 improved. In contrast, oral CS did not change eNO among seven patients with acute vascular rejection (with or without LB). A randomized but open-label study of heart-lung transplant recipients suggested that nebulized budesonide 1 g b.i.d. × 12 months may protect against the development of OB in patients with recurrent episodes of AR.[342] Five patients received budesonide; oral CS were withdrawn in four and no patients developed OB or deteriorating PFTs. In contrast, OB developed in three of six controls not receiving budesonide; oral CSs were continued in four of six controls. One prospective, double-blind trial randomized 30 LTRs with stable BOS (stage 0) at 3 to 9 months posttransplant to receive either inhaled fluticasone propionate or placebo.[343] The initial phase of the study ran 3 months; 19 patients continued in the long-term follow-up phase. In both the short- and long-term follow-up intervals, there were no advantages to the fluticasone-treated group as compared with placebo. These various studies are inadequate to assess the benefit (if any) of inhaled CS to treat or prevent BOS.

Azithromycin. Macrolide antibiotics exhibit immunomodulatory effects,[344,345] and have been shown to be beneficial in inflammatory bronchiolar or pulmonary disorders (diffuse panbronchiolitis)[346,347] and cystic fibrosis.[348,349] Although data in LTRs are limited, a recent open-label pilot study suggested that oral azithromycin (250 mg three times per week) was beneficial in a small cohort of six LTRs.[350] In that study, mean FEV1 improved in five patients by 0.50 L (increase of 17.1% predicted FEV1 above pretreatment baseline).

Captopril. The angiotensin system can enhance FB proliferation, transformation to myofibroblasts, ECM formation, thus possibly promote fibrosis. In a rodent model, inhibiting the angiotensin-converting enzyme (ACE) attenuated radiation-induced pulmonary endothelial dysfunction and fibrosis.[351] Captopril (an ACE inhibitor) reduced chronic cardiac allograft rejection in rats.[352,353] In a rat tracheal transplant model, heavy staining for ACE in the fibroproliferative lesion was noted in the control group, whereas captopril attenuated OB.[354] Data in humans are lacking, but studies assessing the efficacy of ACE inhibitors in LTRs would be of interest.

Statins. The 3-hydroxy-3 methylglutaryl coenzyme A reductase inhibitors (statins) possess immunomodulatory effects, independent of blood cholesterol lowering,[355,356] and may have a role to prevent allograft rejection.[357] Statins were associated with improved outcomes and graft vasculopathy among cardiac transplant recipients[356,358] but no such benefit was found in renal transplant recipients aside from reduction in blood lipid levels.[359,360,361] A recent retrospective study compared outcomes of 39 LTRs with received statins (prescribed for hyperlipidemia) to a contemporaneous control cohort of 161 LFTs who did not receive these drugs.[357] Among LTRs treated with statins, statistically significant reductions were noted in several parameters, including fewer episodes of acute cellular rejection, fewer inflammatory cells on BAL, and reduced requirements for TRL or CsA. More importantly, none of 15 LTRs started on statins during postoperative year 1 developed OB, whereas the cumulative incidence of OB among controls was 37% (p < 0.01). The 6-year survival was higher among LTRs receiving statins (91%) compared with control subjects (54%, p < 0.01). The excess mortality in the control group was largely attributable to complications of allograft rejection and/or immunosuppressive medications. Although it is possible that these salutorious effects observed with statins may reflect chance or observational bias, the statin and control cohorts were comparable at entry with respect to other potential risk factors for allograft rejection (e.g, donor-recipient MHC mismatches, donor ischemic time, age, donor-recipient CMV status). These data are promising, but enthusiasm should be tempered by potential deleterious reactions associated with statin use. Additional prospective, randomized trials are required before advocating statins for all LTRs.

Alemtuzumab (Campath 1H). Alemtuzumab (campath 1H) is a humanized monoclonal antibody against the CD52 antigen that is expressed on the surface of normal and malignant B cells, T lymphocytes, natural killer cells, monocytes, macrophages, and platelets. This agent has been used to treat B cell CLL (chronic lymphocytic leukemia) refractory to chemotherapy and has been investigated for treatment of acute renal allograft rejection.[362,363] Data with alemtuzumab for treatment of refractory AR in LTR is limited to a single case report.[364]

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