Pathology of pulmonary antibody-mediated rejection: 2012 update from the Pathology Council of the ISHLT.

Acute antibody-mediated rejection (AMR) of the allograft is now recognized as a significant complication after cardiac and renal transplantation. In both the pediatric and adult cardiac transplant populations, AMR is responsible for acute allograft dysfunction and predisposes patients to accelerated development of transplant vasculopathy and graft loss.1, 2, 3, 4 and 5 The diagnosis and management of cardiac AMR have evolved over the last 20 years and the pathologic criteria have recently been enumerated.5 and 6 Over the last decade, there has also been increased attention given to the concept of AMR in the pulmonary transplant population.7 and 8 The consequences of immunologic injury in the form of donor HLA-specific antibodies include the development of persistent/recurrent acute cellular rejection (ACR) of all grades, lymphocytic bronchiolitis (LB), chronic rejection manifested as bronchiolitis obliterans syndrome (BOS) and its histopathologic correlate of obliterative bronchiolitis (OB).9, 10, 11, 12 and 13 A review of the published literature regarding AMR of the lung allograft, however, reveals a limited number of large clinical series and scattered case reports. The true incidence of pulmonary AMR is unknown as definitions, diagnostic criteria and management protocols are lacking. Further, the morphologic manifestations of pulmonary AMR in these reports demonstrated a broad range of histopathologic patterns and terminology. AMR was not formally addressed in the original 1990 or revised 1996 ISHLT working formulation for the diagnosis and classification of lung allograft rejection, except for the recognition in the 1996 edition that the diagnosis of hyperacute rejection (HAR) required a multidisciplinary approach.14 and 15 The 2007 revised working formulation of the International Society for Heart and Lung Transplantation (ISHLT) concluded that histopathologic and immunophenotypic criteria were not yet established or accepted by pathologists.16 Although hyperacute rejection was described as fibrin thrombi and fibrinoid necrosis of the interstitial capillaries with hemorrhage, a spectrum of histopathologic changes manifesting as “capillary injury” was proposed for AMR. It was also emphasized that this pattern of injury was non-specific and could be seen in the setting of harvest/reperfusion injury, infection, moderate and severe acute cellular rejection (ACR) and diffuse alveolar damage (DAD) of any cause. Extrapolating from the renal and cardiac experience it was observed that immunohistochemical staining could be performed on formalin-fixed transbronchial biopsies employing a number of antibodies such as C3d, C4d, CD31 and CD68.16 To accumulate additional experience with immunohistochemical staining of biopsy specimens, systematic study of larger groups of patients are needed to elucidate histopathologic patterns of AMR, determine morphologic mimics of AMR, and to evaluate the potential roles of infection and acute cellular rejection in the development of AMR. Since 2007, there has been growing interest in a multidisciplinary approach to the diagnosis and treatment of pulmonary AMR. Symposia devoted to this topic have been held at the annual scientific meetings of the ISHLT and the Banff conferences, recognizing the need to expand our understanding and approaches to AMR.17 This prompted the Pathology Council of the ISHLT to undertake a detailed review of the current morphologic and immunologic criteria at the 32nd annual meeting and scientific sessions of the ISHLT in Prague, Czech Republic, on April 17, 2012. Herein we present the findings, recommendations and avenues for future investigation from the group of thoracic transplant pathologists who participated in the workshop.