Clinical-pathologic features of humoral rejection in cardiac allografts: a study in 81 consecutive patients

Humoral rejection is an infrequently reported, poorly understood form of cardiac allograft rejection.

We reviewed 81 consecutive heart transplant recipients followed up to 3 years after transplantation to evaluate the frequency and significance of humoral rejection in this population. Histologic features evaluated included capillary endothelial cell swelling, interstitial edema and hemorrhage, and neutrophilic infiltration. Immunofluorescence studies with antibodies to immunoglobulin G, immunoglobulin A, immunoglobulin M, Clq, C'3, HLA-DR, and fibrinogen and immunoperoxidase staining for endothelial cells (factor VIII-related antigen) and macrophages (KP1 [CD68]) were performed. Minimal criteria for the diagnosis of humoral rejection were capillary endothelial cell swelling and any immunoglobulin and complement staining in capillaries. Findings were graded and compared with concurrent hemodynamic measurements.

Immunoperoxidase staining showed that most swollen cells in capillaries were macrophages and fewer were endothelial cells. Humoral rejection was detected in 102 biopsy specimens from 42 patients (52%), within 3 weeks of transplantation in 28, and 3 weeks to 4 months later in the other 14 patients. One patient had evidence of humoral rejection almost 3 years after transplantation. A third of biopsy specimens with humoral rejection were associated with abnormal hemodynamics; of these 33 specimens only five had significant (grade 3 or 4) coexisting cellular rejection. Histologic findings most often associated with hemodynamic abnormalities were diffuse capillary endothelial cell swelling and any interstitial hemorrhage or edema. Three patients died of humoral rejection; only 1 had coexisting cellular rejection (grade 3A).

In our experience humoral rejection (1) is not uncommon (52% of patients), (2) is often (33% of cases) associated with hemodynamic abnormalities, and (3) may be fatal.