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

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 valgan-giclovir 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 sequencing. Translational research platforms that provide rapid molecular genotyping for detection of CMV drug-resistance are essential in guiding CMV disease management in high-risk transplant recipients.