Abstract Background Antibody-mediated rejection (AMR) after lung transplantation represents a significant but challenging-to-diagnose cause of allograft dysfunction. It is typically characterized by the presence of donor-specific antibodies (DSAs), histologic evidence of microvascular injury, and complement deposition, with variable presentations including dyspnea, cough, fever, hemoptysis, hypoxemia, and respiratory failure. The coexistence of diffuse alveolar hemorrhage (DAH), ANCA positivity, and class II DSA elevation without prior vasculitis is highly unusual. We present a case highlighting the diagnostic complexity of distinguishing among alloimmune injury, infection, and autoimmune vasculitis. Case Presentation A 65-year-old man with chronic obstructive pulmonary disease underwent bilateral lung transplantation in 2023, complicated by chronic lung allograft dysfunction and persistently elevated class II HLA-DQ4 DSAs. He presented with acute hemoptysis. Computed tomography chest angiography revealed acute pulmonary embolism, bronchiolitis obliterans, upper lobe ground-glass opacities, and lower lobe consolidative opacities. Bronchoscopy confirmed DAH. Laboratory evaluation showed a high-titer c-ANCA (1:640) but negative MPO and PR3 antibodies, and urinalysis revealed no hematuria. His immunosuppressive regimen included tacrolimus, mycophenolate mofetil, and prednisone. Sputum cultures grew Pseudomonas aeruginosa and metapneumovirus. Given concurrent infection, ANCA-associated vasculitis (AAV) was considered less likely; however, the overlap with elevated DSAs raised suspicion for an alloimmune-mediated process. He was treated with high-dose methylprednisolone, plasmapheresis, and intravenous immunoglobulin (IVIG), with resolution of hemoptysis. Rituximab was deferred due to active infection. The patient remained stable on baseline immunosuppression and a slow prednisone taper. Discussion Lung AMR is increasingly recognized as a major cause of graft dysfunction and a contributor to chronic lung allograft dysfunction (CLAD). Class-II DSAs, particularly against human leukocyte antigen (HLA)-DQ and HLA-DP genes, play a central role in rejection. Genetic studies have implicated class-II HLA alleles (DP, DQ, DR) with AAV. Although DAH is classically associated with ANCA vasculitis, it may also result from immune-mediated capillaritis secondary to AMR. In this case, infection likely acted as an inflammatory trigger in a sensitized host with pre-existing DSAs. This case illustrates a rare presentation of DAH in a lung transplant recipient with concurrent c-ANCA positivity and elevated class II DSAs, suggesting an overlap between AMR and capillaritis. Recognition of atypical AMR presentations is essential for timely intervention and improved graft outcomes. This abstract is funded by: None
Kim et al. (Fri,) studied this question.