Temporal Relationship Between Diffuse Alveolar Hemorrhage and Detection of Dq-Dsas in Lung Transplant Recipients

Abstract

After lung transplant (LTx), donor specific antibodies (DSAs) to anti-human leukocyte antigen (HLA) play an important role in antibody mediated rejection (AMR) and subsequent allograft dysfunction. DSAs amplify the immune response via complement-dependent and independent pathways leading to poor outcomes. Diffuse alveolar hemorrhage (DAH) is a lifethreatening condition with dismal outcomes that is known to complicate hematopoietic stem cell transplant (HCT). Although its etiology remains unknown, lung tissue inflammation causing disruption of the alveolar-capillary membrane and cytokine release is implicated in DAH pathogenesis. DAH has not been previously linked to DSA formation in LTx; a temporal relation may exist between the two processes resulting in negative outcomes.METHODS: retrospective chart review of 100 LTx done over 3 years, revealed 3 patients with DAH post-LTx. Cases included bilateral and single LTx. All patients had induction and post-transplant immunosuppression as per standardized institution protocols. Anti-HLA antibodies were tested using Single Antigen Bead and C1q assays (One Lambda, Canoga Park, CA) and all cases had 0% cPRA class I & II and negative HLA pre-transplant. Post-transplant courses were complex, including primary graft dysfunction, pneumonia leading to respiratory failure. DAH was diagnosed clinically and via bronchoscopy with biopsy within 2 to 4 weeks of LTx. Treatment included pulse steroids and intravascular immunoglobulins infusions (IVIg). RESULTS:DSAs became positive over a period of 1 to 6 months. All patients developed class II DQ4 and DQ7 DSAs with two patients having positive C1q. They were treated with IVIg and rituximab or bortezomib. Plasmapheresis was not performed. One patient successfully cleared DSAs. Two patients died and 1 progressed to RAS-CLAD this was irrespective of DSA clearance. CONCLUSIONS:It is essential to understand the risk factors for de novo DSA formation to prevent AMR post LTx. In this case series DAH likely triggered the development of DQ-DSAs secondary to tissue damage and release of donor antigens. Once formed, DSAs caused significant morbidity and mortality. This sample is small, and all patients had other potential causes for DSA development, a temporal relationship between DAH & DSA formation likely exists. Additional investigations are needed to understand this process and develop treatment protocols. In a recent publication, DAH in HCT patients receiving modest amounts of steroids had better outcomes, this may be beneficial in LTx recipients and could be studied further. Physicians must remain vigilant in managing these patients CLINICAL IMPLICATIONS: DAH triggering DSA formation is an area that needs further study amongst all solid organ transplant recipients specifically in LTx. LTx is known to have inferior survival outcomes, and identifying contributing causes helps develop better treatment protocols.