Purpose. The most recent International Society for Heart and Lung Transplantation (ISHLT) biopsy scale classifies cellular and antibody-mediated rejections. However, there are cases with acute decline in left ventricular ejection fraction (LVEF ≤ 45%) but no evidence of rejection on biopsy. Characteristics and treatment response of this biopsy negative rejection (BNR) have yet to be elucidated. Methods. Between 2002 and 2012, we found 12 cases of BNR in 11 heart transplant patients as previously defined. One of the 11 patients was treated a second time for BNR. Characteristics and response to treatment were noted. Results. 12 cases (of 11 patients) were reviewed and 11 occurred during the first year after transplant. 8 cases without heart failure symptoms were treated with an oral corticosteroids bolus and taper or intravenous immunoglobulin. Four cases with heart failure symptoms were treated with thymoglobulin, intravenous immunoglobulin, and intravenous methylprednisolone followed by an oral corticosteroids bolus and taper. Overall, 7 cases resulted in return to normal left ventricular function within a mean of 14 ± 10 days from the initial biopsy. Conclusion. BNR includes cardiac dysfunction and can be a severe form of rejection. Characteristics of these cases of rejection are described with most cases responding to appropriate therapy. 1. Introduction Heart transplantation continues to provide patients with end-stage heart disease with extended survival with a half-life of 9.3 years between 2000 and June 2008. [1]. However, despite substantial advancements in immunosuppression, patients continue to be at significant risk for allograft rejection early after cardiac transplantation. The two recognized forms of allograft rejection are acute cellular rejection and antibody-mediated rejection (AMR). While acute cellular rejection has historically been the most common cause of allograft dysfunction, AMR has only recently become widely accepted [2]. During the 2004 International Society of Heart and Lung Transplantation (ISHLT), cellular rejection grades were revised and AMR was formally defined [3]. In April 2010, a publication from the ISHLT Consensus Conference assessed the status of AMR in heart transplantation and a pathologic grading scale was devised [4]. Despite the advent of new technology, such as gene expression profiling and echocardiograms, endomyocardial biopsy remains the standard for detecting rejection. To minimize the risk of a false negative, multiple specimens (usually 3–5) are obtained from 3 different sites. Though rare, false
References
[1]
J. Stehlik, L. B. Edwards, A. Y. Kucheryavaya et al., “The registry of the international society for heart and lung transplantation: twenty-seventh official adult heart transplant report—2010,” Journal of Heart and Lung Transplantation, vol. 29, no. 10, pp. 1089–1103, 2010.
[2]
M. C. Fishbein and J. Kobashigawa, “Biopsy-negative cardiac transplant rejection: etiology, diagnosis, and therapy,” Current Opinion in Cardiology, vol. 19, no. 2, pp. 166–169, 2004.
[3]
S. Stewart, G. L. Winters, M. C. Fishbein et al., “Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection,” Journal of Heart and Lung Transplantation, vol. 24, no. 11, pp. 1710–1720, 2005.
[4]
G. J. Berry, A. Angelini, M. M. Burke et al., “The ISHLT working formulation for pathologic diagnosis of antibody-mediated rejection in heart transplantation: evolution and current status (20052011),” Journal of Heart and Lung Transplantation, vol. 30, no. 6, pp. 601–611, 2011.
[5]
R. Bhalodolia, C. Cortese, M. Graham, and P. J. Hauptman, “Fulminant acute cellular rejection with negative findings on endomyocardial biopsy,” Journal of Heart and Lung Transplantation, vol. 25, no. 8, pp. 989–992, 2006.
[6]
T. R. Zerbe and V. Arena, “Diagnostic reliability of endomyocardial biopsy for assessment of cardiac allograft rejection,” Human Pathology, vol. 19, no. 11, pp. 1307–1314, 1988.
[7]
M. X. Pham, J. J. Teuteberg, A. G. Kfoury et al., “Gene-expression profiling for rejection surveillance after cardiac transplantation,” The New England Journal of Medicine, vol. 362, no. 20, pp. 1890–1900, 2010.
[8]
Y. L. Wu, Q. Ye, K. Sato, L. M. Foley, T. K. Hitchens, and C. Ho, “Noninvasive evaluation of cardiac allograft rejection by cellular and functional cardiac magnetic resonance,” JACC, vol. 2, no. 6, pp. 731–741, 2009.
[9]
Y. L. Wu, Q. Ye, D. F. Eytan et al., “MRI investigation of macrophages in acute cardiac allograft rejection after heart transplantation,” Circulation, 2013.
[10]
G. M. Pieper, A. Shah, L. Harmann, B. C. Cooley, I. A. Ionova, and R. Q. Migrino, “Speckle-tracking 2-dimensional strain echocardiography: a new noninvasive imaging tool to evaluate acute rejection in cardiac transplantation,” The Journal of Heart and Lung Ttransplantation, vol. 29, no. 9, pp. 1039–1046, 2010.
[11]
C. A. Labarrere and B. R. Jaeger, “Biomarkers of heart transplant rejection: the good, the bad, and the ugly,” Translational Research, vol. 159, no. 4, pp. 238–251, 2012.
[12]
J. Abrams, O. Amir, W. B. Etheridge, and O. H. Frazier, “Histologic findings proving the existence of humoral rejection in a cardiac allograft,” Cardiovascular Pathology, vol. 16, no. 1, pp. 38–42, 2007.
[13]
J. Kobashigawa, J. K. Patel, M. Kittleson et al., “Esmailian F. 530 biopsy-negative rejection: an official new ISHLT rejection category,” The Journal of Heart and Lung Transplantation, vol. 30, pp. S178–S179, 2011.
[14]
J. Jarcho, D. C. Naftel, T. W. Shroyer et al., “Influence of HLA mismatch on rejection after heart transplantation: a multiinstitutional study,” Journal of Heart and Lung Transplantation, vol. 13, no. 4, pp. 583–596, 1994.
[15]
X. Zhou, W. H. Barber, C. K. Moore et al., “Frequency distribution of cytochrome p450 3a4 gene polymorphism in ethnic populations and in transplant recipients,” Research Communications in Molecular Pathology and Pharmacology, vol. 119, no. 1–6, pp. 89–104, 2006.
