The Impact of NOD2/CARD15, TLR and IL23R Polymorphisms on the Incidence of Infectious Complications in Allo-HSCT Recipients.
Authors: Holowiecka-Goral Alexandra Maria , Giebel Sebastian , Wojnar Jerzy , Pietruszka Elzbieta , Karolczyk Agnieszka , Soja Anna , Czerw Tomasz , Holowiecki Jerzy , Krawczyk-Kulis Malgorzata , Markiewicz Miroslaw , Mendrek Wlodzimierz , Stella-Holowiecka Beata , Kyrcz-Krzemien Slawomira 
Published: April 2020

Abstract
BACKGROUND: Infections and graft-vs.-host disease (GvHD) remain the major obstacles for successful allogeneic stem cell transplantation (alloHSCT). As specific immune response is profoundly suppressed during the first months after transplantation, the components of innate immunity are expected to play important role in protection against infections and modulation of GvHD. The goal of this prospective study was to evaluate the impact of NOD2/CARD15 gene, toll-like receptors (TLR), and interleukin-23 receptor (IL-23R) single nucleotide polymorphisms (SNPs), on outcome of alloHSCT, including the incidence of infectious complications and acute GvHD. All these factors were documented to take part in innate immunity.
PATIENTS: One-hundred-twenty-five consecutive patients, mainly with hematological malignancies, aged 32 (18–58)y, treated with alloHSCT from HLA-matched related (n=43) or matched unrelated donor (MUD) (n=82) were analyzed. The conditioning regimen was myeloablative, GVHD prophylaxis consisted of cyclosporin, metotrexate, and, in case of MUD-HSCT, pre-transplant anti-thymocyte globulin.
METHODS: Donors and recipients were tested for SNP8,12,13 of the NOD2/CARD15 gene, TLR2/753, TLR4/299, TLR4/399, TLR5/C1174T, and TLR9/1635 SNPs, as well as IL23R/11209026 SNP. Study end-points included the incidence of bacterial, fungal and clinically relevant viral infections. Infections were recognized based on clinical symptoms, microbial cultures, chest X-rays for pneumonia confirmation and in case of CMV and EBV- PCR screening. We analyzed separately infections occurring in the early, cytopenic phase and those occurring after engraftment. Additionally, the incidence of acute GvHD and survival was evaluated.
RESULTS: Presence of NOD2/CARD15 SNP8 in recipient resulted in higher frequency of neutropenic pneumonia (40% vs. 6%, p=0.045) and bacterial pharyngitis (100% vs. 50%, p=0.06), as well as increased incidence of grade III-IV acute GVHD (40% vs. 7%, p=0.05), which translated into increased non-relapse mortality (60% vs. 14%, p=0.005) and decreased 2-year overall survival (20% vs. 71%, p=0.003). TLR4/299 SNP in recipient tended to increase the risk of neutropenic fever (FUO) (67% vs. 30%, p=0.06) and decrease survival (71% vs. 48%, p=0.09). TLR2/753 SNP in donor was associated with higher incidence of FUO (83% vs. 30%, p-0.01), while TLR5/C1174T SNP in recipient resulted in increased incidence of EBV infection (25% vs. 4%, p-0.05). Presence of IL23R/11209026 SNP in donor tended to increase the incidence of neutropenic pneumonias (29% vs. 6%, p=0.09).
CONCLUSIONS: NOD2/CARD15, TLR, and IL23R SNPs appear to influence outcome of alloHSCT contributing to increased incidence of infections, and in case of NOD2/CARD15 SNP8 in recipient to increased risk of severe acute GVHD. The genomic analysis may allow elaboration of adequate preventive strategies based on individual risk assessment. Our results encourage for further, extended studies.