April Case of the Month Clinical History:

A 62-year-old male patient underwent bilateral lung transplantation for connective tissue disease-associated interstitial lung disease (CTD-ILD). He had a significant 10-year history of gastroesophageal reflux disease (GERD) complicated by a Grade 4 hiatus hernia. Pre-transplant immunologic evaluations, including single-antigen bead (SAB) testing for HLA class I and II antibodies, virtual crossmatch, and flow cytometry-based lymphocyte crossmatch, were all negative. Three weeks post-transplant, he successfully underwent a planned laparoscopic fundoplication without complications.

However, six weeks after transplantation, the patient presented with new-onset fatigue and a mild increase in his oxygen requirements. High-resolution computed tomography (HRCT) of the chest demonstrated bilateral ground-glass opacities (GGOs), raising concerns for potential infection, acute rejection, or early antibody-mediated rejection (AMR). Diagnostic bronchoscopy with bronchoalveolar lavage (BAL) microbiologic analysis returned negative for bacterial, mycobacterial, fungal, and viral pathogens. Repeat SAB testing, however, revealed the emergence of high mean fluorescence intensity (MFI) donor-specific antibodies (DSAs) against HLA Class II antigens: DQA1*06:01 (MFI 13,600; cutoff 1,000) and DQA1*03:01 (MFI 9,560; cutoff 1,000).

Given persistent allograft dysfunction, fluoroscopy-guided transbronchial lung biopsy (TBLB) was performed from the anterior segment of the right lower lobe. Histologically, the biopsy consisted of six fragments of well-expanded, alveolated lung parenchyma along with bronchial walls and blood vessels (Fig 2). Examination revealed interstitial edema (Fig 3) with moderate inflammatory infiltrate composed predominantly of lymphomononuclear cells, macrophages, and scattered neutrophils (Fig 4). Capillary inflammation (capillaritis) was prominent, characterized by back-to-back neutrophils and focal nuclear fragmentation (Fig 5, 6). Additionally, focal intra-alveolar fibrin deposits and Type II pneumocyte hyperplasia were noted (Fig 7). Large airways (Fig 8) and blood vessels (Fig 9) were unremarkable, without perivascular inflammation characteristic of acute cellular rejection (ACR) (Fig 10). No evidence of lymphocytic bronchiolitis, aspirated material, granuloma formation, viral cytopathic changes, or malignancy was observed. Special stains for mycobacterial (AFB) and fungal organisms (GMS) were negative. Immunohistochemistry (IHC) for cytomegalovirus (CMV) was negative, whereas C4d staining demonstrated focal circumferential endothelial positivity in less than 50% of capillaries (Fig 11).

Based on the clinical presentation, positive DSAs, characteristic histologic findings, and focal C4d endothelial positivity, the patient was diagnosed with definite antibody-mediated rejection (AMR) according to the International Society for Heart and Lung Transplantation (ISHLT) criteria. He subsequently received treatment with plasmapheresis, intravenous immunoglobulin (IVIG), and bortezomib. .

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