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JAC Advance Access published online on January 22, 2004
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkh065
© 2004 by The British Society for Antimicrobial Chemotherapy
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© 2004 The British Society for Antimicrobial Chemotherapy

Brief report

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

Fausto Baldanti 1 , Daniele Lilleri 2 , Giulia Campanini 2 , Giuditta Comolli 1 , Anna Lisa Ridolfo 3 , Stefano Rusconi 3 , and Giuseppe Gerna 2 *

1 Servizio di Virologia and Laboratori Sperimentali di Ricerca, IRCCS Policlinico San Matteo, 27100 Pavia;
2 Servizio di Virologia, IRCCS Policlinico San Matteo, 27100 Pavia;
3 Istituto di Malattie Infettive e Tropicali, Università degli Studi di Milano, Ospedale Luigi Sacco, Milan, Italy

* Corresponding author. E-mail: g.gerna{at}smatteo.pv.it.

Received 25 July 2003 ; revised 28 October 2003 ; accepted 10 November 2003

Abstract

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/recipient-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.

Keywords: HCMV, drug resistance, D+R-, CD4 cell response
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