Cytokine Profiles of Pre-Engraftment Syndrome after Single-Unit Cord Blood Transplantation for Adult Patients

Abstract

Clinical manifestation of high-grade fever and skin rash before neutrophil engraftment, termed pre-engraftment syndrome (PES) or pre-engraftment immune reaction, has been frequently observed after cord blood transplantation (CBT). The pathophysiology of PES is poorly understood, but cytokine storm during the early phase of CBT is thought to be 1 of the main cause of PES. However, the cytokine profiles of PES after CBT are unclear. Therefore, we examined the relationship between serum cytokine profiles and PES in 44 adult patients who received CBT in our institution between February 2013 and June 2016. Serum levels of 21 cytokines, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL-17A, IL-17F, IL-18, IL-21, IL-22, IL-23, IL-33, monocyte chemoattractant protein-1, IFN-α, IFN-γ, and TNF-α, were measured by multiplex bead assays using a flow cytometer. The median time until the absolute neutrophil count was >.5 × 10/L was 21 days (range, 15 to 41 days). The cumulative incidence of PES was 79.6% (95% confidence interval, 63.3% to 88.5%) at 60 days after CBT. Serum levels of IL-5 (P = .009) and IL-6 (P = .01) at 2 weeks were significantly higher in patients who developed PES compared with those who did not develop PES. The conversion from naïve to effector or central memory phenotype of T cells was observed in PES. These data indicate that elevations of IL-5 and IL-6 around the time of clinical manifestation may be possible biomarkers for PES after CBT.

Engraftment syndrome following hematopoietic stem cell transplant: A review of the literature

“…In a prospective review of 56 pediatric HSCTs, Khandelwal et al 4 reported a significant increase in IL‐6 in the ES group compared to non‐ES patients. Furthermore, Yanagisawa et al 15 recognized IL‐6 elevations in their retrospective review of 27 pediatric patients and Konuma et al 14 identified elevations in IL‐5 and IL‐6 at two weeks following cord blood transplant for patients diagnosed with ES.…”

“…The release of pro‐inflammatory cytokines manifests in direct and indirect cellular necrosis. The major cytokines involved are thought to include interleukin‐1, interferon‐gamma, and tumor necrosis factor alpha 8,12‐15 . There is dramatic variation in the reported incidence of ES with the majority of authors identifying a range between 5% and 79% 13,14,16,17 …”

“…Contention remains regarding risk factors and treatment regimen for ES 4,13,14,22 . This literature review explores ES following HSCT in relation to these areas.…”

Platelet Transfusion Refractoriness in Single-Unit Cord Blood Transplantation for Adults: Risk Factors and Clinical Outcomes

“…Our data showed that a median 16-hour CCI was significantly lower 16 to 30 days after CBT, which is around the potential onset period of pre-engraftment syndrome (PES). PES is a unique clinical manifestation of fever, skin rash, and CRP elevation that occurs before neutrophil engraftment [26,27]. PES has frequently been observed during this period after CBT.…”

Single cord blood transplantation in Japan; expanding the possibilities of CBT

“…The mechanisms underlying PIR or HPS have not been clarified. Serum values for inflammatory cytokines such as IL-6 or IL-5, are elevated around the time of PIR onset [46,47]. We previously showed that rapid T cell chimerism switches to the donor type, and phenotypic conversion from naïve to memory T cells are significantly associated with the development of PIR [48].…”