Unknown cytomegalovirus serostatus in primary immunodeficiency disorders: A new category of transplant recipients

Abstract

Background Cytomegalovirus (CMV) serostatus of recipient (R) and donor (D) influences hematopoietic stem cell transplant (HSCT) outcome. However, it is not a reliable indicator of CMV infection in primary immunodeficiency disorder (PIDD) recipients who are unable to make adequate antigen‐specific immunoglobulin (Ig) or who receive intravenous Ig (IVIg) prior to testing. Objective Since no data exist on PIDD with unknown CMV serostatus, we aimed to evaluate the relationship between pre‐HSCT recipient and donor serostatus and incidence of CMV infection in recipients with unknown serostatus. Methods A retrospective analysis of all pediatric PIDD HSCTs (2007‐2018) was performed at University of California San Francisco. Recipients were separated into categories based on pre‐transplant serostatus: 1) seropositive (R(+)), 2) seronegative (R(‐)), and 3) unknown serostatus (R(x)). Patients with pre‐HSCT active CMV viremia were excluded. Results A total of 90 patients were included, 69% male. The overall incidence of CMV infection was 20%, but varied in R(+), R(‐), and R(x) at 80%, 0%, and 14%, (P‐value = .0001). Similarly, 5‐year survival differed among groups, 60% R(+), 100% R(‐), and 90% of R(x) (P‐value = .0045). There was no difference in CMV reactivation by donor serostatus (P‐value = .29), however, faster time to clearance of CMV was observed for R(x)/D(+) group (median 9.5 days (IQR 2.5‐18), P‐value = .024). Conclusion We identify a novel group of recipients, R(x), with an intermediate level of survival and CMV incidence post‐HSCT, when compared to seropositive and seronegative recipients. No evidence of CMV transmission from D(+) in R(‐) and R(x) was observed. We believe R(x) should be considered as a separate category in future studies to better delineate recipient risk status.

Cytomegalovirus in the transplant setting: Where are we now and what happens next? A report from the International CMV Symposium 2021

“…The need for agents targeting other replication steps has resulted in identification of maribavir that acts on the UL97 viral kinase and letermovir that acts on terminase proteins. In the SOLSTICE trial, maribavir resulted in higher rates of CMV clearance in HSCT and SOT recipients with refractory/resistant CMV than therapy with polymerase inhibitors 5,49 . Letermovir also shows promise as a salvage therapy, but resistance can develop rapidly, especially if patient compliance is poor or treatment is interrupted 50…”

“…Per Ljungman reminded delegates that a CMV-positive recipient coming in for HSCT has a lower chance of survival than CMV-negative individuals when other factors (i.e., age) are taken into consideration. 5,6 This impact on survival can either be a direct consequence of CMV disease (i.e., end-organ disease or systemic viral infection) or an indirect outcome resulting from an increased risk of opportunistic bacte-rial, viral or fungal infection, graft rejection, thrombotic events, or cardiovascular disease. [7][8][9][10] Poor survival is not only associated with CMV status in the recipient, as using stem cells from a CMV-positive donor in a CMV-negative recipient also increases the risk of mortality.…”

“…Early studies demonstrated some effectiveness with acyclovir and valaciclovir, and while ganciclovir and foscarnet are effective, there are concerns relating to toxicity with these agents in HSCT 24–26 . However, he explained that letermovir has been shown to result in a significant reduction in clinically significant CMV infection in HSCT and also in all‐cause mortality 5,27 . All‐cause mortality was an exploratory endpoint in the letermovir prophylaxis study in HSCT recipients, and a significant difference between letermovir and placebo was seen at Week 24 (10.2% and 15.9%, respectively, p = .03) 27 .…”

Impact of cytomegalovirus infection prior to hematopoietic stem cell transplantation in children with inborn errors of immunity

“…Another strategy that could reduce mortality is the selection of cytomegalovirus-seropositive donors, given that cytomegalovirus-specific memory T-cells transferred from the graft can help control the infection [ 32 ]. Nevertheless, the majority of data on cytomegalovirus infection in HSCT recipients are derived from patients with hematological malignancies [ 11 ]. In our cohort, although most infected patients received grafts from cytomegalovirus-seropositive donors, morbidity and mortality remained very high.…”

“…In contrast, cytomegalovirus infections in immunocompromised patients can be life-threatening [ 9 ]. Cytomegalovirus is the most frequent viral pathogen in patients diagnosed with IEI prior to HSCT and is a risk factor for pre- and post-HSCT morbidity and mortality [ 9 – 11 ]. Cytomegalovirus disease prior to HSCT appears to be significantly more common in patients with IEI than in patients who undergo HSCT for other diseases, due to their profound pre-procedural lymphopenia and/or functional lymphocyte defects [ 1 , 7 – 9 ].…”