Portal de Periódicos da CAPES

Case Report

2012; Wolters Kluwer; Volume: 93; Issue: 7 Linguagem: Inglês

10.1097/tp.0b013e318249b163

1534-6080

Petra Goldsmith, Mir Mubariz Husain, Andrew Carmichael, Hongyi Zhang, Stephen Middleton,

Parvovirus B19 Infection Studies

Cytomegalovirus (CMV) donor+/recipient− multivisceral transplantation is at significant risk of complicated primary CMV infection which is normally countered by anti-CMV drug prophylaxis (1). We describe a rare case of multidrug-resistant CMV that emerged in a multivisceral allograft recipient. CASE REPORT In October 2008, a 34-year-old Caucasian woman with a history of familial adenomatous polyposis, intra-abdominal desmoid disease, obstructive uropathy, and superior vena caval thrombosis received a cluster graft consisting of small intestine, stomach, pancreas, and kidney from a CMV IgG-positive donor. Pretransplant, she was CMV IgG-negative. She made a good early postoperative recovery and was discharged on standard CMV prophylaxis of oral valganciclovir 900 mg daily for 5 months. Nine months posttransplantation, she developed asymptomatic CMV viremia which peaked at 6.16(log10) copies/mL and responded to intravenous ganciclovir. Subsequently, oral valganciclovir prophylaxis was resumed, and the viral load remained undetectable. However, 14 months posttransplantation, she was readmitted because of worsening diarrhea and renal impairment. Intestinal graft biopsies showed severe acute cellular rejection, necessitating treatment with intravenous methylprednisolone 500 mg daily for 3 days, followed by oral prednisolone 20 mg twice daily. Due to continued diarrhea, she received intravenous alemtuzumab (Campath-1H) 30 mg on days 8 and 12 of the admission after which the rejection resolved. Recurrence of CMV viremia occurred on day 13 at 3.8(log10)copies/mL, which was probably caused by significant lymphopenia (0.01×109/L) secondary to alemtuzumab and reduced bioavailability of oral valganciclovir, proxied by a subtherapeutic tacrolimus level of 2.8 μg/L. Intravenous ganciclovir was recommenced, but the CMV load increased further. At that time, viral genotyping did not identify drug resistance mutations. After 3 months of intravenous ganciclovir, during which the CMV load was repeatedly undetectable, oral valganciclovir prophylaxis was recommenced. However, within a month, viremia recurred, increasing to 6.2(log10)copies/mL 20 months posttransplantation despite conversion to intravenous ganciclovir. At the time of CMV reactivation, serum tacrolimus levels were therapeutic (8–13 μg/mL) and intestinal biopsies were normal, suggesting adequate valganciclovir absorption. Repeat viral genotyping detected the C603W mutation in the UL97 gene associated with resistance to ganciclovir; no foscarnet resistance mutations were detected.FIGURE 1: Cytomegalovirus (CMV) progression over time.CMV viremia persisted despite changing to foscarnet, which she tolerated for 6 weeks until she developed renal impairment. Subsequently, she was treated with three doses of intravenous cidofovir with no impact on the viremia but with further deterioration in renal function. Viral genotyping at 22 months posttransplantation now detected the C603W mutation and two new mutations; the L545S mutation in the UL54 gene associated with resistance to both ganciclovir and cidofovir and the Q578H mutation associated with foscarnet resistance. Previous case reports suggest that leflunomide may be effective against drug-resistant CMV (2, 3). She was treated with leflunomide 100 mg daily for 3 days, then a maintenance dose of 20 mg daily, after which the viremia declined but was still detectable at low levels (<4 (log10) copies/mL). The patient developed worsening symptoms of sensory peripheral neuropathy, and because leflunomide was a potential cause of these symptoms, it was discontinued 24 months posttransplant. The patient remained asymptomatic with low level CMV viremia off antiviral therapy. Following cessation of antiviral drugs, the maintenance dose of tacrolimus immunosuppression was reduced and the immunosuppressive effect induced by previous administration of alemtuzumab decreased with time; lymphocyte levels increased to more than 109/L at 23 months posttransplant. Serum anti-CMV IgM and IgG antibodies, previously negative at 14 and 18 months posttransplantation, became positive at 24 months posttransplant, indicating seroconversion. Over the following month, the serum concentration of anti-CMV IgG increased while the plasma CMV viremia decreased toward the lower limit of detection over the next 3 months. Thereafter, the CMV viral load remained undetectable to 36 months follow-up. DISCUSSION Transplantation-associated ganciclovir-resistant CMV has a prevalence ranging from 0.1% to 20% (4, 5). Multidrug-resistant CMV is rare. Multivisceral allograft recipients may be at particularly high risk of developing drug-resistant CMV because of the more intense immunosuppression they receive and the reduced oral bioavailability of valganciclovir when intestinal rejection develops (6, 7). Ganciclovir resistance in this patient leads to difficulties in her management because of adverse effects caused by foscarnet and cidofovir. Resistance to ganciclovir is inferred by mutations in the UL97 phosphotransferase, whereas mutations in UL54 polymerase can cause cross resistance to foscarnet and cidofovir (8, 9). The evolution of multiple resistance mutations made standard agents ineffective. Leflunomide targets virion assembly and is a potentially viable alternative to suppress viral replication (2, 3). After reducing immunosuppression, the long-term control of CMV viremia was eventually achieved by the delayed generation of recipient T cell and antibody responses to CMV. Petra M. Goldsmith Mir Mubariz Husain Andrew Carmichael Hongyi Zhang Stephen J. Middleton Department of Surgery Cambridge University Hospitals NHS Foundation Trust Cambridge Cambridgeshire, United Kingdom HPA Clinical Microbiology and Public Health Laboratory Cambridge University Hospitals NHS Foundation Trust Cambridge Cambridgeshire, United Kingdom Department of Infectious Diseases Cambridge University Hospitals NHS Foundation Trust Cambridge Cambridgeshire, United Kingdom HPA Clinical Microbiology and Public Health Laboratory Cambridge University Hospitals NHS Foundation Trust Cambridge Cambridgeshire, United Kingdom Department of Gastroenterology Cambridge University Hospitals NHS Foundation Trust Cambridge Cambridgeshire, United Kingdom