Revisiting Cytomegalovirus Serology in Allogeneic Hematopoietic Cell Transplant Recipients

Abstract

Background Allogeneic hematopoietic cell transplant recipients (allo-HCTR) with positive CMV serology may have false positive results due to blood product transfusions associated passive immunity. Methods This is a single-center cohort study including consecutive adult allo-HCTR (01.01.2018-31.12.2022) with negative baseline (at hematologic malignancy diagnosis) and indeterminate or low-positive (CMV-IgG-titer: ≥ 0.6-<50 U/mL) pretransplant CMV-serology with negative pretransplant plasma CMV DNAemia. The CMV serology status of those patients was reclassified from R + to R- (CMVR- reclassification group). We compared those patients to allo-HCTR with negative (CMV-IgG-titer < 0.6 U/mL) pretransplant CMV IgG serology (CMVR- group). We describe the number and type of patients, whose pretransplant CMV serology status was reclassified from indeterminate/positive to negative. Moreover, we reviewed all plasma CMV DNAemia tests performed during the first 6 months posttransplant in both groups, to assess the safety of this approach. Results Amongst 246 (84.5%) of 291 transplanted patients identified as CMVR + pretransplant, 60/246 (24.4%) were reclassified from CMV serology indeterminate (N:10) or low-positive (N:50) to R-. Only 1/60 (1.67%) patient in the CMVR- reclassification group vs 3/44(6.8%; p = 0.30) in the CMVR- group developed CMV-DNAemia during the 6-month posttransplant follow-up period. There were no significant differences in the number of CMV-DNAemia tests performed, CMV-DNAemia range and time posttransplant between the two groups. Conclusion One out of four allo-HCT CMVR + may be falsely flagged as R+, with significant impact on donor selection and prophylaxis administration. A 2-step approach including CMV-serology testing at hematologic malignancy diagnosis in allo-HCTR candidates and careful review of pretransplant CMV IgG-titers may help correctly classify CMV-serology status.

Routine Infectious Disease Consultation Prior to an Allogeneic Hematopoietic Cell Transplant

“…Third, CMV-R serology was reinterpreted from indeterminate/low IgG titer positive to negative in 60 of 292 (20.5%) patients with negative CMV serology at the time of hematologic malignancy and an indeterminate (between 0.6 and 3 U/mL; n = 10 [16.7%]) or low positive (between >3 and <50 U/mL; n = 50 [83.3%]) pretransplant CMV IgG titer and negative pretransplant CMV DNAemia. Among them, only 1 patient (1/60 [1.6%]) developed a positive plasma CMV DNAemia during 6-month follow-up posttransplant, attributed to either CMV-positive donor or a new primary CMV infection posttransplant [ 4 ].…”

“…In that respect, CMV serology is routinely reviewed in our center at the time of the TID consultation and compared (when available) with the CMV serology at the time of the hematologic malignancy diagnosis. We identified 60 patients whose CMV serology was negative at the time of their underlying hematologic malignancy diagnosis and who had an indeterminate or low positive IgG titer at the time of their pretransplant TID consultation [ 4 ]. As patients remain mostly hospitalized and at low risk to develop a primary CMV infection between the diagnosis of their hematologic malignancy and their transplant, we considered those serologies as “false-positive,” due to passive immunity in the context of immunoglobulin or blood transfusions, and reclassified the CMV recipient status from positive to negative in all those patients, with only 1 of the 60 patients with reclassified CMV serology developing CMV DNAemia posttransplant [ 4 , 17 ].…”

“…Major interventions were defined as (1) HCT cancellation or postponement, (2) any diagnostic or therapeutic invasive procedure recommended before HCT (eg, bronchoscopy, surgical procedure), and (3) reinterpretation of the recipient cytomegalovirus (CMV) serostatus. Regarding the latter, recipients with a negative CMV serology at the time of their underlying hematologic malignancy diagnosis and an indeterminate or positive with a low immunoglobulin G (IgG) titer (≥0.6 to <50 U/mL) CMV serology and negative pretransplant plasma CMV DNAemia at the time of their TID consultation were considered to have a negative CMV serology, attributed to passive immunity because of blood product transfusions [ 4 ]. Hence, they were labeled and considered as CMV recipient negative for their allogeneic HCT [ 4 ].…”

“…Regarding the latter, recipients with a negative CMV serology at the time of their underlying hematologic malignancy diagnosis and an indeterminate or positive with a low immunoglobulin G (IgG) titer (≥0.6 to <50 U/mL) CMV serology and negative pretransplant plasma CMV DNAemia at the time of their TID consultation were considered to have a negative CMV serology, attributed to passive immunity because of blood product transfusions [ 4 ]. Hence, they were labeled and considered as CMV recipient negative for their allogeneic HCT [ 4 ]. Minor interventions included (1) consultation requests with other specialist services, (2) additional diagnostic test requests, (3) additional treatment recommendations for already existing or newly diagnosed infectious diseases, (4) other-than-CMV recipient serology reinterpretation (eg, Toxoplasma gondii , hepatitis A virus [HAV], or hepatitis B virus [HBV] surface antibody indeterminate or low positive IgG titers at the time of TID consultation with negative results at the time of hematologic malignancy diagnosis), (5) changes of standard anti-infective prophylactic recommendations, and (6) changes of standard empirical antibiotic treatment recommendations in case of neutropenic fever post-HCT.…”

Reexploring cytomegalovirus serology in allogeneic hematopoietic cell transplantation

“…The last two years have seen a renewed interest in the importance of CMV immunoglobulin G ( IgG) titers in allogeneic HCT recipients, suggesting that a dichotomous interpretation of CMV serology as positive or negative may not necessarily be an accurate and sufficient interpretation. In contrast, quantification of CMV IgG titers may allow for correct interpretation of CMV status of allogeneic HCT recipients and predict CMV DNAemia posttransplant [ 5 ▪▪ , 6 , 7 ▪▪ , 8 , 9 ▪ , 10 ▪ ]. Herein, we report on the most recent data on the importance of CMV IgG titers in the allogeneic HCT setting and future perspectives.…”