LAUSR

Chronic lung allograft dysfunction (CLAD) is the major barrier to better longterm survival in lung transplant recipients, and treatment options remain limited.1 The efficacy of azithromycin for the treatment and prevention of CLAD has been demonstrated in retrospective and randomized controlled studies, and this has become widely accepted as firstline therapy.2-5 However, the clinical response is not dramatic, and many patients have progressive allograft dysfunction resulting in allograft failure and death. Antithymocyte globulin and corticosteroids are other potential treatments for CLAD; however, these strategies have not been validated in largescale or randomized clinical trials, and their efficacy is unclear.6 A role for extracorporeal photopheresis (ECP) in the management of CLAD has been recognized for over 20 years.7-9 Although the exact mechanism of ECP remains unclear, the expansion of regulatory T cells to promote a tolerogenic profile appears to be a key component. ECP has also been associated with a reduction in both donorspecific HLA antibodies and antibodies to lungrestricted selfantigens.10 Isenring et al11 here present longterm followup of 21 lung transplant recipients treated with ECP, including nine treated for bronchiolitis obliterans syndrome (BOS) and 12 treated for recurrent acute cellular rejection (ACR). In this study, those treated with ECP for ACR had superior survival to those treated with ECP for BOS. In addition, those treated for BOS had better survival when ECP was started at an early stage of BOS. It is difficult to compare outcomes of lung recipients with recurrent ACR to those who develop CLAD because CLAD is the leading cause of death beyond the first year after transplant while ACR is rarely fatal.1 Although recurrent ACR has been a consistent risk factor for the development of CLAD, survival analyses of patients with recurrent ACR compared to those with CLAD and the comparison of survival of those with different BOS stages are limited by leadtime bias. In other words, it is difficult to draw conclusions about the relative efficacy of ECP in earlystage BOS from these data. Of note, none of the patients in either group was treated with antithymocyte globulin, alemtuzumab, or other intensive immunosuppression for recurrent ACR or CLAD. Additionally, as the authors note, this study is limited by the small sample size and retrospective design. Lastly, ongoing use of ECP treatment was limited by cost and reimbursement in this cohort, as has been the case for many patients in the USA. Ultimately, Isenring et al present a descriptive study evaluating the use of ECP for two different forms of lung allograft rejection. As there are alternative and more practical treatment modalities for recurrent ACR such as highdose corticosteroids, antithymocyte globulin and alemtuzumab, the potential role for ECP is most compelling for the treatment of CLAD. However, it is noteworthy that none of the patients treated with ECP for recurrent ACR in Isenring et al’s cohort developed BOS. Recurrent ACR has been consistently recognized as an important risk factor for the development of CLAD. Thus, the findings of Isenring et al suggest that treatment with ECP may ameliorate this risk. Unfortunately, cost has limited widespread access to ECP and has made designing largescale multicenter clinical trials difficult. Additionally, it would be nearly impossible to conduct a doubleblinded study of ECP. Going forward, largescale clinical trials are necessary to validate the efficacy and safety of ECP for CLAD. Given the incidence of CLAD in lung transplant recipients and the morbidity and mortality associated with CLAD, it is imperative that more effective therapeutic modalities be identified and put into widespread clinical use. Furthermore, clinical trials should be sufficiently powered to study differences in the response to ECP between obstructive and restrictive CLAD phenotypes, identify predictors of a clinical response, and better characterize the effect of ECP on humoral alloreactivity, including circulating donorspecific HLA antibodies and antibodymediated rejection.