Surgical treatment of a foscavir-resistant atypical Cytomegalovirus pneumonia in an allogeneic stem cell transplant recipient.

Pulmonary infections are a major cause of morbidity and mortality after allogeneic stem-cell transplantation (allo-SCT). Invasive aspergillosis is one of the major causes of pulmonary infection, but viruses are frequently involved, particularly human Cytomegalovirus (CMV). Because of impaired cellular immunity, the risk for pulmonary infections is greatest during the early post engraftment period (from day 30 to 100). However, pulmonary infections also occur during the late phase (>100 days), and in particular in patients who developed acute or chronic graft versus host disease (GVHD) treated by steroids. Pre-emptive strategies are now widely used for prevention of CMV disease in allo-SCT patients. Ganciclovir (GCV), and more recently valganciclovir (VGCV) are the most commonly used drugs. However, late CMV disease still occurs, and prolonged antiviral therapies and/or recurrent viral reactivation episodes may lead to the emergence of resistant virus strains. Resistance mutations are located within the UL97 kinase and/or DNA polymerase (UL54) viral genes. In the absence of large prospective studies, the incidence of CMV resistance after allo-SCT is unknown. We report here a case of atypical CMV pneumonia after allo-SCT which was resistant to antiviral therapy and successfully treated by surgery. Miss B. is a 64 year-old woman diagnosed with Ph positive chronic myeloid leukemia at a blastic phase in february 2005. A major molecular (2.10-5) response was obtained after imatinib therapy and she underwent alloSCT from an HLA phenoidentical unrelated donor in december 2005 (d0). The non-myeloablative conditioning regimen included total body irradiation and fludarabine. She received antithymocyte globulin, cyclosporine, and mycophenolate mofetil for graft versus host disease (GVHD) prophylaxis. She was also given valaciclovir (VACV, 3 g/d) for the prevention of herpes simplex virus infections. Both patient and donor were CMV seropositive. CMV DNAemia was monitored by in house real time quantitative PCR (adapted from ref. #8). At d28, she developed histologically confirmed grade IIIIV9 GVHD. She was successfully treated with steroids. At d45, a first CMV reactivation occurred and was preemptively treated by sequential GCV/VGCV therapy (Figure 1). CMV viral load (VL) became negative at d76. At d90, while still under steroids (2 mg/kg), she presented cutaneous grade III GVHD treated by PUVA therapy, in association with the other immunosuppressors (mycophenolate mofetil and ciclosporine). At d180, while she was under VACV, she presented with hyperthermia, thrombosis and pulmonary embolism, associated with high CMV VL (4.4 log10cop/10 peripheral blood leukocytes [PBL]). In addition to anti thrombotic therapy, she received VGCV at curative dose for 14 days, followed by maintenance therapy. Low viral replication (<3 log10cop/10 PBL) persisted under VGCV, and a GCVresistant strain was detected by UL97 genotyping in blood at d220. The resistance mutation was retrospectively detected in blood from d180 (Table 1). Because of diarrhea (d229), biopsies were performed and histological examination revealed CMV colitis. Alternative therapy with foscavir was initiated and permitted a significant decrease of CMV DNAemia (<2,5 log10cop/10 PBL) associated with partial regression of colitis symptoms. From d200, Miss B presented a chronic hacking cough. The first two computed tomography (CT) scans at d238 and 250 did not show any distinctive lesions. Pulmonary aspergillosis was suspected on the third CT at d292, that showed a unique pulmonary mass located in the upper right lobe (Figure 1). Aspergillosis antigenemia and bronchoalveolar lavage remained negative. Nevertheless she Haematologica online only 2008