Human cytomegalovirus double resistance in a donor-positve/recipient-negative lung transplant patient with an impaired CD4-mediated specific immune response

Background: Emergence of human cytomegalovirus (HCMV) resistance to ganciclovir in solid-organ transplant recipients has been found to be mostly associated with primary HCMV infection. Materials and methods: The case of a donor-positive/recipeent-negative (D⁺/R^-) lung transplant patient developing ganciclovir and cidofovir resistance is described. HCMV infection was monitored by weekly determination of antigenaemia, viraemia and DNAaemia. HCMV-specific CD4 cell immunity was determined by cytokine flow cytometry. The emergence of drug-resistant HCMV strains was documented by sequencing of UL97 and UL54 genes of HCMV directly in blood samples. Results: Following primary HCMV infection, the patient showed repeated reactivations for over a year, eventually resulting in the selection of a ganciclovir-resistant HCMV strain with a mutation in the UL97 gene product (A594V). Determination of HCMV-specific CD4 cell immunity showed a persistently impaired immune response. Subsequent foscarnet treatment allowed only transitory virus clearance from blood owing to renal toxicity. Further ganciclovir treatment induced a new mutation in both UL97 (H520Q) and UL54 (P522S) with final emergence of double resistance to both ganciclovir and cidofovir. The patient eventually died of lung failure. Discussion: Determination of HCMV-specific CD4 cell immunity could be of help in predicting the emergence of drug-resistant strains in D⁺/R^-transplant recipients.