Persistent primary cytomegalovirus infection in a kidney transplant recipient: Multi-drug resistant and compartmentalized infection leading to graft loss

Abstract

Cytomegalovirus (CMV) is one of the most common opportunistic infections after transplantation. To prevent CMV infections, universal prophylaxis and pre-emptive therapy with ganciclovir or its prodrug valganciclovir is applied. However, prolonged antiviral therapy may result in drug-resistance emergence. We describe a case of a 43-year-old CMV-seronegative patient who underwent kidney transplantation from a CMV-seropositive donor and developed CMV disease despite valganciclovir prophylaxis. CMV viral load increased even though valgangiclovir dose was augmented and immunosuppressive therapy reduced. CMV genotyping revealed mutations in the viral UL97 protein kinase, explaining ganciclovir-resistant CMV infection. The viral load failed to respond to foscavir, cidofovir and CMV-neutralizing immunoglobulins. Kidney allograft dysfunction developed 3 months post-transplantation with a histopathologic diagnosis of CMV nephropathy and potentially concomitant T-cell mediated rejection. A transplantectomy was performed on day 164 post-transplantation since the patient had uncontrollable CMV disease associated with a circulating multidrug-resistant DNA polymerase-mutant virus. Detailed monitoring in this patient demonstrated hallmarks of complicated CMV disease: (i) relatively rapid evolution of drug-resistant CMV mutants in the setting of persistent high blood viral loads, (ii) emergence of viral drug-resistance linked to acute graft rejection, (iii) transient and, thereafter, lack of response to various anti-CMV treatments, (iv) compartmentalization and heterogeneity of CMV viral populations, (v) possible differential ability of viral mutants to cause disease in the graft, and (vi) detection of minor viral variants by next generation

New Perspectives on the Immunopathogenesis and Treatment of Uveitis Associated With Vogt-Koyanagi-Harada Disease

“…Efforts to corroborate the latter findings failed so far and the ensemble of such studies cautions that an association does not necessarily represent a cause ( 42 ). In this respect, the type of body fluid analyzed (vitreous vs. cerebrospinal fluid) may be critical to detect the presence of viruses, as it is known that even in single patients different strains of viruses may be compartmentalized at specific locations ( 37 , 43 ).…”

Management of ganciclovir resistance cytomegalovirus infection with CMV hyperimmune globulin and leflunomide in seven cardiothoracic transplant recipients and literature review

“…These include the CMV serostatus (D+/R-), type of transplanted organ, dose and duration of valGCV (VGCV) prophylaxis, peak viral loads and the intensity of immunosuppressive therapy. 4,5 GCV resistance (GanR) stems from mutations affecting the UL97 gene, which encodes the viral DNA phosphotransferase that monophosphorylates GCV, and/or the UL54 gene, which encodes viral DNA polymerase. 6 Different UL97 mutations result in a variable degree of GCV resistance and response to antiviral dose increments.…”