Association between the kinetics of cytomegalovirus reactivation evaluated in terms of the area under the curve of cytomegalovirus antigenemia and invasive mold infection during the post‐engraftment phase after allogeneic hematopoietic stem cell transplantation

Abstract

Background: We evaluated the clinical impact of cytomegalovirus (CMV) reactivation calculated in terms of the area under the curve of CMV antigenemia (CMV-AUC) on the development of invasive mold infection (IMI) in the post-engraftment phase after allogeneic hematopoietic stem cell transplantation (HSCT). Methods: Among 394 consecutive patients who underwent their first allogeneic HSCT at our center between 2007 and 2018, 335 were included after excluding patients with a past history of invasive fungal disease (IFD), the development of IFD before engraftment, engraftment failure, or early death within 30 days. CMV antigenemia (CMV-AG) was monitored weekly after engraftment and 3 or more cells/2 slides were regarded as positive. CMV-AUC was calculated by the trapezoidal method using the number of CMV-AG after logarithmic transformation and the duration in weeks and was added until negative conversion. Patients with CMV reactivation were divided into low and high CMV-AUC groups using the median value of CMV-AUC as a threshold. Results: There were 17 proven/probable IMIs including one mucormycosis and 16 probable invasive aspergillosis, and the 2-year cumulative incidence was 1.0% in the negative CMV-AUC group (n = 136), 3.3% in the low CMV-AUC group (n = 98) and 13.8% in the high CMV-AUC group (n = 101) (P = .001). In a multivariate analysis, grade II-IV acute GVHD (HR 3.74) and CMV-AUC (HR low 1.25, high 5.91) were identified as independent significant factors associated with a higher incidence of IMI. Conclusions: Cytomegalovirus kinetics evaluated in terms of CMV-AUC were significantly associated with the development of IMI in the post-engraftment phase after allogeneic HSCT. How to cite this article: Kimura S-I, Takeshita J, Kawamura M, et al. Association between the kinetics of cytomegalovirus reactivation evaluated in terms of the area under the curve of cytomegalovirus antigenemia and invasive mold infection during the post-engraftment phase after allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis.

Association between the kinetics of cytomegalovirus reactivation in terms of the area under the curve of cytomegalovirus antigenemia and non‐relapse mortality after allogeneic hematopoietic stem cell transplantation

“…In addition, CMV‐AUC might be a surrogate marker of immunosuppresion caused by GVHD and corticosteroid usage. In fact, our previous study showed that CMV‐AUC was associated with the development of invasive mold infection during the postengraftment phase after allogeneic HSCT 32 . Surprisingly, grades II–IV or III–IV acute GVHD were not related to NRM or OS in this study.…”

The association of cytomegalovirus infection and cytomegalovirus serostatus with invasive fungal infections in allogeneic haematopoietic stem cell transplant recipients: a systematic review and meta-analysis

“…32 Kimura et al reported that the area under the curve of CMV antigenemia was an independent factor associated with IFI development. 36 Martino et al J o u r n a l P r e -p r o o f reported 20 out of 37 patients with IFIs had preceding CMV infection. 41 Two studies demonstrated that CMV infection significantly increased the risk of IFI based on multivariable logistic regression.…”

“…A total of 18 studies were extracted for the systematic review. 16,[29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] Six articles were excluded from meta-analysis due to lack of HR. 32,34,36,38,41,45 Accordingly, 12 studies were included for meta-analysis of post-transplant CMV and IFIs.…”

“…16,[29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] Six articles were excluded from meta-analysis due to lack of HR. 32,34,36,38,41,45 Accordingly, 12 studies were included for meta-analysis of post-transplant CMV and IFIs. 16, 29-31, 33, 35, 37, 39, 40, 42-44 Among the 6 studies that were not included in meta-analysis, Bochud et al study contained 2 cohorts that described 4 out of 33 patients with invasive aspergillosis (IA) had preceding CMV disease in the Discovery Study, and 8 out of 103 patients with IA had preceding CMV disease in the Validation Study.…”

“…Visual evaluation of the funnel plots and the results of Egger's regression did not show evidence of publication bias (Figure S3). Among six studies that were not included for meta-analysis, five studies 32,36,38,41,45 concluded that CMV significantly increased the risk of subsequent IFIs in allo-HSCT recipients.…”