Severe Cardiac Allograft Dysfunction Without Endomyocardial Biopsy Signs of Cellular Rejection: Incidence and Management A. Veiga Barreiro, M. Crespo Leiro, N. Dome ´nech Garcı´a, M.J. Paniagua, E. Va ´ zquez Martul, M. Gonza ´lez Cuesta, C. Ramı´rez, A. Juffe ´ Stein, and A. Castro Beiras ABSTRACT Acute dysfunction of cardiac allograft without evidence of cellular rejection is a potentially fatal complication of heart transplantation that suggests a humoral origin. In clinical practice, humoral rejection (HR) is suspected when there is evidence of severe allograft dysfunction but endomyocardial biopsy (EMB) shows no evidence of cellular rejection. Between April 1991 and August 2003, 12 patients (2.74%) among 438 heart transplants displayed this condition. Time post– heart transplant (HT) was 21.3  24.7 months (range 2 to 72 months). Immunofluorescence studies using classic markers were negative. All patients were treated with methylprednisolone “bolus” and plasmapheresis until clinical recovery, after which their immunosuppressive regimens were modified. Eleven of the 12 patients recovered satisfactory allograft function. In this series the incidence of suspected HR was low. Unlike other studies, we observed HR not only soon but also even years after HT. Plasmapheresis seems to be an effective treatment. H UMORAL REJECTION (HR; antibody-mediated rejection) is an infrequent but potentially fatal form of acute allograft rejection. 1 In one study, biopsy findings of HR were associated with acute hemodynamic compromise in 47% of patients, HR was the direct cause of death in 13%. 2 Although Hammond et al 3,4 initially described crite- ria for the diagnosis of HR on endomyocardial biopsy (EMB), other authors were unable to reproduce their results. 5 It seems more useful to use diagnostic markers such as C4d. 6 High levels of antibodies to human vascular endothelial cells also correlate with HR (as diagnosed by EMB criteria) as well as with decreased survival and an increased incidence of coronary allograft vasculopathy. 7 However, there is no consensus on the biopsy-based diag- nosis of HR. 8 From the clinician’s point of view, the incidence and management of HR are not well defined and differ among centers. In clinical practice humoral rejection is suspected when there is evidence of severe allograft dysfunction, but the EMB shows no evidence of cellular rejection and an ischemic etiology can be excluded. In these cases we evaluate endomyocardial biopsy using hematoxylin-eosin (HE) staining of paraffin-embedded fragments and immu- nofluorescence (IF) analysis of frozen tissue with antibodies to IgM, IgG, IgA, C1q, C3, fibrinogen, and albumin. METHODS We retrospectively reviewed the 438 heart transplants (HT) per- formed between April 1991 and August 2003 for patients showed severe hemodynamic compromise, as defined by the presence of systolic dysfunction, congestive heart failure, or low output needing catecholamines, mechanical ventilation, and/or intra-aortic ballon pumping. Humoral rejection was officially suspected if the EMB showed no cellular rejection and coronary angiography, no evi- dence of either vasculopathy or acute myocardial infarction. In these cases, the IF studies described above were performed on frozen tissue at the time of EMB. All patients suspected of suffering HR were treated with meth- ylprednisolone “bolus” and subjected to plasmapheresis (one ses- sion per day, minimum seven) until clinical recovery, after which their therapeutic and immunosuppressive regimens were modified. Azathioprine was replaced with cyclophosphamide or mycopheno- late mofetil, and cyclosporine with tacrolimus. From the Department of Pathology (A.V.B., M.G.C., E.V.M.), Area of the Heart (M.C.L., M.J.P., C.R., A.J.S., A.C.B.), and Investigation Unit (N.D.G.), CHU Juan Canalejo, and Healthy Science Institute (A.C.B.), A Corun ˜ a, Spain. Address reprint requests to Jesu ´ s Alberto Veiga Barreiro, Department of Pathology, CHU Juan Canalejo, As Xubias de Arriba 84, PC: 15006, A Corun ˜ a, Spain. E-mail: veigabarreiro@canalejo.org 0041-1345/04/$–see front matter © 2004 by Elsevier Inc. All rights reserved. doi:10.1016/j.transproceed.2004.03.033 360 Park Avenue South, New York, NY 10010-1710 778 Transplantation Proceedings, 36, 778 –779 (2004)