Recurrent Late Cytomegalovirus Disease after Hematopoietic Cell Transplantation (HCT): Incidence, Clinical Manifestations, Risk Factors and Outcome

Background: Late cytomegalovirus (CMV) disease occurs in about 6% of patients (R+ or D+/R-) who survive the first three months after HCT.We have previously identified steroid treatment after day 100 and CMV viremia before and after day 100 as risk factors for late CMV disease. Little is known, however, about the epidemiology and risk factors of recurrent late CMV disease.The objectives of this study were to describe the incidence, clinical characteristics, outcome, and risk factors for the development of recurrent late CMV disease.

Methods: We retrospectively analyzed medical records of 117 HCT patients, who developed CMV disease more than 100 days after their first allogeneic HCT between 2001 and 2011.We evaluated all CMV disease events occurring between the first late CMV disease and 2 years after HCT.Late CMV disease was considered recurrent if it occurred at least 6 weeks after the first late CMV disease.

Results: Among 117 patients with late CMV disease, 31 (26%) patients died within 6 weeks of diagnosis. Twelve of the eighty-six (14%) surviving patients developed a second late CMV disease event. Nine (75%) of the second late CMV disease cases were observed in the same organ, while three (25%) occurred in a different organ. There were 6 (50%) cases of gastrointestinal (GI) disease, 5 (42%) cases of pneumonia, and 1 (8%) episode of retinitis. Second late CMV disease episodes occurred at a median of 147 days [range 52-351] after the first late CMV disease and 374 days [range 212-679] after HCT. In addition, there were 4 cases of third late CMV disease (3 pneumonia and 1 GI).

All of the patients were receiving systemic immunosuppressive therapies at the time they developed recurrent late CMV disease. Nine of these twelve patients were undergoing weekly surveillance for viremia by PCR testing after their first late CMV disease event. Two patients developed CMV disease while receiving preemptive therapy for viremia. Three patients had low-level viremia below the threshold for starting treatment. However, four (33%) of the recurrent late CMV disease events (2 pneumonia, 2 GI) developed in the absence of viremia.

Two (17%) of the 12 patients with recurrent late CMV disease died within 6 weeks of their diagnosis; one additional patient died shortly after developing a third episode of CMV disease, and the remaining 9 patients survived at least to two years after HCT.

Conclusions:  These data demonstrate that recurrent late CMV disease is not a rare event after allogeneic HCT. Patients who remain on systemic immunosuppressive therapy after a first episode of late CMV disease seem to be at particularly high risk for recurrence.  While preemptive treatment of viremia might prevent some of these events, one-third of the cases developed in the absence of viremia including 2 cases of CMV pneumonia.  Further study is warranted to prevent the morbidity and mortality associated with this late complication of HCT.