CMV and EBV Reactivation Post HSCT Impairs Survival of Patients If They Do Not Produce IgM Antibodies Againts These Viruses

Abstract 4552

It is known that CMV infection/reactivation influences the survival of patients post HSCT. Risk factors are associated with both (i) the CMV serostatus of donors and recipients and (ii) the immunological potential of the recipients post transplantation.

In this study 142 patients - 69 males and 73 females suffering from hematological malignancies, SAA and inborn errors at the age from 0.6 to 64 (median 40) - were followed for the presence of CMV and EBV DNA copies and the presence of CMV and EBV IgM antibodies in blood post HSCT (61 sibling and 81 matched unrelated donors) with 625 days of median observation time. In addition the number of lymphocytes in blood and the proportions and numbers of CD4, CD8, CD20 positive cells in blood were analyzed in association with the CMV and EBV findings.

CMV and EBV DNA copies were determined with the use of qPCR at 1-week intervals until 30 day post HSCT, then monthly until one year post HSCT and then at routine follow-up examinations (usually in 3 months intervals), and always when clinically suggested. Values exceeding 50 copies/10^5 cells were recognized as positive and clinically significant. At the same time the presence of IgM and IgG antibodies specific for CMV and EBV were examined with the use of ELISA. The first positive results for CMV DNA copies were seen at median time of 48 days post-transplant and IgM antibodies if present were detected in a majority of cases within 30 days after DNA copies finding. EBV copies were detected at the similar time post transplantation (median day of positive results: 48 days) and IgM antibodies if present were usually seen within 2 months after DNA copies detection. Notably, in 9 patients EBV reactivations were associated by the appearance of IgM CMV but not EBV antibodies. Therefore the presence of IgM antibodies against either CMV or EBV was recognized as a sign of the ability of a given patient to respond immunologically to CMV or EBV viruses.

For the sake of this study the patients group was divided into subgroups as follow: (1) CMV and/or EBV copies present but IgM antibodies absent, (2) CMV and/or EBV DNA copies as well as CMV and/or EBV antibodies present, (3) neither CMV or EBV copies nor IgM antibodies present, (4) CMV and EBV DNA copies absent but IgM CMV and/or EBV antibodies present.

Patients lacking DNA copies or having both copies and IgM antibodies against CMV and/or EBV had significantly better survival than those having DNA copies but lacking IgM antibodies any time during observation period (2 yrs survival 70% vs 41%, p<0.001). To dissect the influence of the immune response against these two viruses similar evaluation was performed for CMV and EBV separately. It became apparent that the worst survival (Kaplan-Meier overall survival curve) had pts with CMV copies but lacking IgM antibodies (2 yrs survival 73% vs 40%, p=0.001), with respect to EBV similar tendency was observed but less pronounced (2 yrs survival 73% vs 44%, p=0.108).

To understand the immunological background to this observation lymphocytosis and blood lymphocyte subsets were analyzed at 30 day post HSCT. It became apparent that pts having CMV and/or EBV copies but lacking IgM antibodies had significantly lower number of lymphocytes and their (CD4+ cells subset) in blood as compared to patients having IgM antibodies against CMV and/or EBV irrespective whether they had CMV and/or EBV DNA copies with median values as follow: 650/ul (128/ul) vs 370/ul (60/ul), p=0.020 (p=0.033) or lacked CMV and EBV DNA copies, LYM (CD4+) median values: 750/ul (161/ul) vs 370/ul (60/ul), p=0.047 (p=0.060).

CMV and EBV infection/reactivation affects the survival of patients post HSCT if they are unable to generate IgM antibodies against these viruses. Inability to mount humoral response to CMV and EBV was associated with an impairment of the immune system potential (low number of lymphocytes and CD4+ cells in blood).

Supported by the grants N R13 0082 06 from the Polish Ministry of Science & Higher Education.