A 50 year-old presented with a 3 day history of malaise and fatigue 2 months after receiving a deceased donor kidney transplant with T-cell depleting induction therapy. Discharge medications after transplantation included tacrolimus, mycophenolate mofetil, prednisone, and valganciclovir for cytomegalovirus (CMV) prophylaxis. Of note, the patient received a seropositive (D+, CMV IgG positive) organ and was seronegative (R-, CMV IgG negative) herself.
On presentation, physical examination and basic laboratory testing were unremarkable – kidney function remained at baseline with a creatinine of 2.2 mg/dL. Despite valganciclovir prophylaxis, she was found to have a CMV viral load of almost 500,000 IU/mL.
Replication of CMV, a DNA virus and member of the Herpesviridae family, in kidney transplant recipients can be asymptomatic (subclinical CMV infection) or symptomatic and manifest as “CMV disease.” CMV disease is further classified into tissue-invasive CMV disease (with organ involvement) – most commonly causing enteritis or colitis, but also hepatitis, retinitis, meningitis, pneumonitis or allograft nephritis. CMV disease without organ involvement typically presents with fever, malaise, myalgia, leukopenia, or thrombocytopenia, similar to our patient.
After one week of intravenous (IV) ganciclovir therapy, the patient’s symptoms began to improve – though the serum CMV viral load increased to over 1 million IU/mL. CMV anti-viral resistance (to first-line therapy) should be suspected if the CMV viral load fails to decrease, rises or persists beyond 2 weeks of adequate therapy. The most common antiviral resistance encountered is that to ganciclovir, although resistance can be seen to all agents. The most important risk factor for resistance is CMV mismatch D+/R- status. Other known risk factors include chronic immunosuppression and suboptimal of ganciclovir.
CMV drug resistance testing most commonly checks for mutations in 2 genes, the UL97 kinase and the UL54 DNA polymerase. These mutations encode for a viral kinase that mediates triphosphorylation of ganciclovir into the active ganciclovir triphosphate and the CMV DNA polymerase, respectively. This polymerase is a target for all three anti-CMV drugs, ganciclovir, foscarnet and cidofovir.
In this patient, CMV resistance testing failed to detect a mutation. After 2 weeks of treatment with ganciclovir, the CMV viral load decreased and the patient was discharged with 900 mg oral valganciclovir twice daily. Treatment should be continued for at least 2 weeks or until the viral load is undetectable – whichever is longer. Guidelines suggest discontinuing therapy after one negative CMV PCR (using the highly sensitive quantitative nucleic acid amplification assay).
CMV viremia and disease continue to carry high risk of morbidity and mortality and can significantly impact graft function. As the clinical presentation can be variable, recognition and appropriate treatment are crucial to optimize transplant outcomes.