Incidence, Nature, Risk Factors and Outcomes of Cytomegalovirus Infection After Double-Unit Cord Blood Transplantation

           

Background: While CB transplantation (CBT) recipients are at significant risk for CMV infection, the course of this infection after CBT is not well understood. Methods: We examined the incidence, nature, risk factors & outcomes of CMV infection in 154 double-unit CBT recipients transplanted between 10/2005 & 5/2012. Patients received low dose acyclovir as prophylaxis & were monitored for CMV reactivation in the blood by antigenemia assay or qPCR. End-organ disease was diagnosed by standard criteria. Additionally, patients with severe pulmonary compromise in the setting of viremia not fulfilling criteria for CMV pneumonia were defined as CMV pulmonary syndrome. Results: 154 patients [median age 41 years (range 0.9-69), median weight 67 kg (range 8-125), 83 (54%) CMV seropositive] were transplanted for hematological malignancies with myeloablative (n = 118, 77%) or non-myeloablative (n = 36, 23%) conditioning & calcineurin-inhibitor/ mycophenolate mofetil immunosuppression. No patient received anti-thymocyte globulin. CB grafts were 4-6/6 HLA-A,B antigen, -DRB1 allele matched to the recipient. CMV reactivation was restricted to CMV seropositive patients. Of CMV+ CBT recipients monitored by antigenemia (n = 56), 37 (66%) patients reactivated (median onset 40 days, range -1-294). Of these, 7/37 (19%) developed disease with their initial reactivation: 1 pneumonia (onset 58 days), 1 pulmonary syndrome (onset 39 days), & 5 gastrointestinal (GI) disease (median onset 54 days, range 49-67). Notably, all 27 CMV+ patients monitored by PCR reactivated at a median of 33 days (range 3-64). Of these, 4/27 (15%) patients developed CMV disease (1 pneumonia & 3 pulmonary syndrome) at a median of 38 days (range 10-56). None had GI disease with their initial infection. In Cox regression analysis including patient age, diagnosis, conditioning intensity, engrafting unit infused CD34+ dose & engrafting unit-recipient HLA-match, no factor was associated with the risk of severe initial CMV infection (disease or pulmonary syndrome). Recurrent infection has been observed in 29 patients, to date, with reactivation occurring in the context of GVHD and its therapy in 19/29 (66%) patients. With a median 34 months (range 5-79) follow-up of CMV+ patients, CMV infection has caused (n = 2, both pneumonia) or contributed (n = 7) to death in a total of 9 of the 83 (11%) CMV+ patients, with 7/9 deaths occurring with the initial CMV infection. Conclusions: CMV infection remains a major cause of morbidity & mortality in seropositive CBT recipients. PCR surveillance permits earlier detection of reactivation but whether this improves the clinical outcome requires further investigation. CMV-associated lung disease, in particular, remains a serious problem. New strategies for CMV prophylaxis & therapy, and studies of the determinants of CMV-specific immune recovery, are a priority for this patient population.