Cytomegalovirus (CMV) Infection after Umbilical Cord Blood Transplantation and Evaluation of Donor Screening Strategies.
Authors: Albano Maria S. , Taylor Patricia E. , Pass Robert F. , Scaradavou Andromachi , Ciubotariu Rodica , Carrier Carmelita , Dobrila Ludy , Rubinstein Pablo , Stevens Cladd E. 
Published: October 2019

Introduction: Despite the reduction of CMV disease with anti-viral therapy, CMV infection is still considered an important complication of allogeneic stem cell transplantation. CMV status is relevant for selection of the best suitable donor and FDA rules require testing donors for evidence of infection due to CMV. For adult bone marrow donors CMV status is determined by the presence of antibodies to CMV (CMV-Ab). However, there is no consensus on strategies to determine CMV status in cord blood (CB) donors. The interpretation of CMV-Ab in CB donors is complicated because of active transport of maternal IgG across the placenta. Additionally, IgM CMV-Ab is not detectable in most of the infants.

Aim: To assess the incidence of CMV infection after CB transplantation and evaluate strategies for screening CMV in CB donors including maternal serology, culture of infant’s saliva and polymerase chain reaction in CB (CB-PCR).

Methods: Recipients (Rc) of CB units from the National Cord Blood Program (n=1221), were evaluated for post-transplant incidence of CMV infection and risk factors. CB donors (n= 26,988) were evaluated for CMV by culture of saliva. Subgroups were then divided in case-control studies to evaluate the usefulness of PCR to detect CMV-DNA in CB plasma and leukocytes of infants with positive and negative CMV-saliva culture (case-control study 1 and 2 respectively). Mothers of CB donors were tested for CMV-Ab.

Results: Post-transplant CMV infection, reported in 23% of CB Rc, was associated with Rc pre-transplant CMV serology (RR 6.0 p<0.001), but not with CB donor CMV serology. Additionally, CMV infection was associated with HLA mismatch (1MM; RR=3.0; p=0.011; 2–3 MM; RR= 2.8 p=0.017) and severe acute GvHD (RR = 1.7, p < 0.001). Patients who engrafted and had CMV infection had higher risk of secondary graft failure than those without a CMV infection (7.5% vs 1.9%, p <0.001). Overall, CMV was reported as a cause or a contributing cause of death in 6.4% of the Rc that died. Regarding strategies for screening CMV in CB donors, 47 of 26,988 infants had positive saliva culture. In case-control study 1, 33/47 infants with saliva culture positive had a positive CB-PCR while all 90 controls were PCR negative. All mothers of the 33 infants with confirmed CMV infection had total-CMV-Ab (79% with high titers) but only 1/3 had IgM-CMV-Ab. Six of the 33 mothers had also positive CMV-nested-PCR in peripheral blood. In case-control study 2, infants born to mothers with IgM-CMV-Ab but had negative culture of saliva were evaluated by CB-PCR. Of those, 5/170 had positive CB-PCR and thus had a possible CMV infection.

Conclusions: The incidence of CMV infection in CB donors was low (0.12%). Maternal serology had poor predictive value for CMV infection in their infant CB donors and bore no detected relationship to CMV infection in CB Rc. CB-PCR was a useful alternative to saliva culture for detecting CMV in CB donors. CB-PCR has the advantage that uses viral-DNA instead of viable virus and can be performed retrospectively. We suggest a potential screening strategy based on testing all mothers for CMV-Ab followed by pre-release CMV-DNA testing of CB units selected for transplantation when the mother has total-Ab and regardless of her IgM-CMV-Ab status. At present, any strategy to detect CMV, whether by culture or PCR, however, is hampered by the lack of an FDA-approved assay to screen CB donors.