CLINICAL USE OF IMMUNOHISTOPATHOLOGIC METHODS FOR THE DIAGNOSIS OF CYTOMEGALOVIRUS HEPATITIS IN HUMAN LIVER ALLOGRAFT BIOPSY SPECIMENS

Background: Cytomegalovirus (CMV) infections are common in Liver transplant recipients, and some of the patients develop CMV hepatitis. Clinically, this condition is difficult to distinguish from acute rejection. The histologic criteria for acute liver graft rejection are well acccepted, but the criteria for the histomorphologic changes in CMV hepatitis vary considerably. We have recently applied immunohistologic examinations, in situ hybridization, and virus isolation for identification of CMV in liver biopsy specimens. Methods: CMV hepatitis was studied with repeated liver biopsies during the first 3 post-transplant months in 57 transplanted liver grafts. The histopathologic changes due to CMV were compared with those of acute rejection in 99 biopsy specimens. CMV-specific monoclonal antibodies (mAbs) were used to detect the presence of CMV antigens by means of immunofluorescence and immunoperoxidase methods. In situ hybridization for the detection of CMV-DNA was performed on the same paraffin-embedded liver specimens. In most cases, fresh, post-transplant liver specimens were also subjected to virus isolation. Results: Although 60% of the liver graft donors were CMV-seropositive, CMV was rarely detected in the perioperatively obtained specimens: 1 of 36 by in situ hybridization only. None of the 21 specimens (21 patients) obtained from diseased liver grafts during the Ist posttransplant month showed evidence of CMV infection. In contrast, 8 of the 42 specimens (42 patients) obtained during the 2nd and 3rd months showed histopathologic signs of a predominant viral cholangitis (4 cases) or viral lobulitis (4 cases). The presence of CMV was ascertained in 7 of these 42 patients (17%). Conclusions: In liver transplant patients with clinical and laboratory signs of liver involvement, the identification of CMV by immunomorphologic methods and/or by virus isolation permitted the diagnosis of CMV hepatitis with the positive and negative predictive values of 0.86 and 1.0, and 1.0 and 1.0 for the former and the latter methods, respectively, as compared with histologic changes. By using immunohistopathologic techniques, it is possible to initiate antiviral therapy early in patients with CMV hepatitis.