Risk Prediction of CMV Reactivation After Allogeneic Stem Cell Transplantation Using Five Non-HLA Immunogenetic Polymorphisms

Overview

Journal Ann Hematol

Specialty Hematology

Date 2022 May 7

PMID 35525883

Authors

Miren Vallejo

Paula Muniz

Mi Kwon

Laura Solan

Rebeca Bailen

Diego Carbonell

Maria Chicano

Julia Suarez-Gonzalez

Pilar Catalan

Jose Maria Bellon

Juan Carlos Trivino

Nieves Dorado

David Gallardo

Jose Luis Diez-Martin

Natalia Ramirez

Carolina Martinez-Laperche

Ismael Buno

Affiliations

Soon will be listed here.

Abstract

Despite advances in the understanding of the pathophysiology of cytomegalovirus (CMV) infection, it remains as one of the most common infectious complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The aim of this study was to determine the genotype of cytokines and chemokines in donor and recipient and their association with CMV reactivation. Eighty-five patients receiving an allo-HSCT from an HLA-identical sibling donor were included in the study. Fifty genes were selected for their potential role in the pathogenesis of CMV infection. CMV DNAemia was evaluated until day 180 after allo-HSCT. CMV reactivation was observed in 51/85 (60%) patients. Of the 213 genetic variants selected, 11 polymorphisms in 7 different genes (CXCL12, IL12A, KIR3DL1, TGFB2, TNF, IL1RN, and CD48) were associated with development or protection from CMV reactivation. A predictive model using five of such polymorphisms (CXCL12 rs2839695, IL12A rs7615589, KIR3DL1 rs4554639, TGFB2 rs5781034 for the recipient and CD48 rs2295615 for the donor) together with the development of acute GVHD grade III/IV improved risk stratification of CMV reactivation. In conclusion, the data presented suggest that the screening of five polymorphisms in recipient and donor pre-transplantation could help to predict the individual risk of CMV infection development after HLA-identical allo-HSCT.

Citing Articles

Cytomegalovirus Infections in Hematopoietic Stem Cell Transplant: Moving Beyond Molecular Diagnostics to Immunodiagnostics.

Gupta C, Mundan N, Das S, Jawed A, Dar S, Dailah H Diagnostics (Basel). 2024; 14(22).

PMID: 39594189 PMC: 11592488. DOI: 10.3390/diagnostics14222523.

Clinical characteristics and outcomes of overt gastrointestinal bleeding in children undergoing haploidentical hematopoietic stem cell transplantation: a single-center retrospective analysis.

Qi S, Zhang L, Chen Z, Wang Z, Ding L, Du Y BMC Pediatr. 2024; 24(1):479.

PMID: 39068438 PMC: 11282719. DOI: 10.1186/s12887-024-04950-5.

Characterization of recurrent cytomegalovirus reactivations post allogenic stem cell transplantation in a population with high seropositivity.

AlQahtani H, Alsuhebany N, Alowais S, AlShehri B, Althemery A, Alghanim A Virol J. 2024; 21(1):149.

PMID: 38956615 PMC: 11218190. DOI: 10.1186/s12985-024-02421-y.

Significance of CMV reactivation in non-allogeneic stem cell transplant patients with cancers: experience of single tertiary care cancer institute.

Mahar U, Jhatial M, Qazi R, Ahmed U, Ahsan B, Bokhari S Virusdisease. 2023; 34(3):383-388.

PMID: 37780907 PMC: 10533462. DOI: 10.1007/s13337-023-00839-6.

Development of a CRISPR-Cas12a rapid diagnostic for human cytomegalovirus.

Monk C, Youngquist B, Brady A, Shaffer J, Hu T, Ning B Antiviral Res. 2023; 215:105624.

PMID: 37150408 PMC: 10280810. DOI: 10.1016/j.antiviral.2023.105624.

References

Martinez-Laperche C, Buces E, Aguilera-Morillo M, Picornell A, Gonzalez-Rivera M, Lillo R . A novel predictive approach for GVHD after allogeneic SCT based on clinical variables and cytokine gene polymorphisms. Blood Adv. 2018; 2(14):1719-1737. PMC: 6058238. DOI: 10.1182/bloodadvances.2017011502. View

Boeckh M, Ljungman P . How we treat cytomegalovirus in hematopoietic cell transplant recipients. Blood. 2009; 113(23):5711-9. PMC: 2700312. DOI: 10.1182/blood-2008-10-143560. View

Jaskula E, Dlubek D, Duda D, Bogunia-Kubik K, Mlynarczewska A, Lange A . Interferon gamma 13-CA-repeat homozygous genotype and a low proportion of CD4(+) lymphocytes are independent risk factors for cytomegalovirus reactivation with a high number of copies in hematopoietic stem cell transplantation recipients. Biol Blood Marrow Transplant. 2009; 15(10):1296-305. DOI: 10.1016/j.bbmt.2009.06.008. View

Zaia J, Sun J, Gallez-Hawkins G, Thao L, Oki A, Lacey S . The effect of single and combined activating killer immunoglobulin-like receptor genotypes on cytomegalovirus infection and immunity after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2009; 15(3):315-25. PMC: 2770248. DOI: 10.1016/j.bbmt.2008.11.030. View

Beziat V, Liu L, Malmberg J, Ivarsson M, Sohlberg E, Bjorklund A . NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs. Blood. 2013; 121(14):2678-88. PMC: 3617633. DOI: 10.1182/blood-2012-10-459545. View

Tu C, Arnolds K, OConnor C, Spencer J . Human Cytomegalovirus UL111A and US27 Gene Products Enhance the CXCL12/CXCR4 Signaling Axis via Distinct Mechanisms. J Virol. 2017; 92(5). PMC: 5809719. DOI: 10.1128/JVI.01981-17. View

Carvalho A, Cunha C, Carotti A, Aloisi T, Guarrera O, Di Ianni M . Polymorphisms in Toll-like receptor genes and susceptibility to infections in allogeneic stem cell transplantation. Exp Hematol. 2009; 37(9):1022-9. DOI: 10.1016/j.exphem.2009.06.004. View

Slade M, Goldsmith S, Romee R, Dipersio J, Dubberke E, Westervelt P . Epidemiology of infections following haploidentical peripheral blood hematopoietic cell transplantation. Transpl Infect Dis. 2016; 19(1). PMC: 5459579. DOI: 10.1111/tid.12629. View

Widmann T, Sester U, Gartner B, Schubert J, Pfreundschuh M, Kohler H . Levels of CMV specific CD4 T cells are dynamic and correlate with CMV viremia after allogeneic stem cell transplantation. PLoS One. 2008; 3(11):e3634. PMC: 2572846. DOI: 10.1371/journal.pone.0003634. View

10.

Casto A, Seo S, Levine D, Storer B, Dong X, Hansen J . Genetic variants associated with cytomegalovirus infection after allogeneic hematopoietic cell transplantation. Blood. 2021; 138(17):1628-1636. PMC: 8554648. DOI: 10.1182/blood.2021012153. View

11.

Karimi M, Motazedian M, Geramizadeh B, Nikeghbalian S, Yaghobi R, Abedi F . Association of the Co-stimulatory Molecules Polymorphisms with CMV Infection in Liver Transplant Recipients. Int J Organ Transplant Med. 2014; 2(4):171-7. PMC: 4089271. View

12.

Loeffler J, Steffens M, Arlt E, Toliat M, Mezger M, Suk A . Polymorphisms in the genes encoding chemokine receptor 5, interleukin-10, and monocyte chemoattractant protein 1 contribute to cytomegalovirus reactivation and disease after allogeneic stem cell transplantation. J Clin Microbiol. 2006; 44(5):1847-50. PMC: 1479205. DOI: 10.1128/JCM.44.5.1847-1850.2006. View

13.

Mezger M, Steffens M, Semmler C, Arlt E, Zimmer M, Kristjanson G . Investigation of promoter variations in dendritic cell-specific ICAM3-grabbing non-integrin (DC-SIGN) (CD209) and their relevance for human cytomegalovirus reactivation and disease after allogeneic stem-cell transplantation. Clin Microbiol Infect. 2007; 14(3):228-34. DOI: 10.1111/j.1469-0691.2007.01902.x. View

14.

Annibali O, Piccioni L, Tomarchio V, Circhetta E, Sarlo C, Franceschini L . Impact of IFN lambda 3/4 single nucleotide polymorphisms on the cytomegalovirus reactivation in autologous stem cell transplant patients. PLoS One. 2018; 13(7):e0200221. PMC: 6056038. DOI: 10.1371/journal.pone.0200221. View

15.

McSharry B, Avdic S, Slobedman B . Human cytomegalovirus encoded homologs of cytokines, chemokines and their receptors: roles in immunomodulation. Viruses. 2012; 4(11):2448-70. PMC: 3509658. DOI: 10.3390/v4112448. View

16.

Sellathamby S, Lakshmi K, Busson M, Viswabandya A, George B, Mathews V . Polymorphisms in the immunoregulatory genes are associated with hematopoietic recovery and increased susceptibility to bacterial infections in patients with thalassaemia major undergoing matched related hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2012; 18(8):1219-26. DOI: 10.1016/j.bbmt.2012.01.011. View

17.

Cano P, Han F, Wang H, Fernandez-Vina M, Han X . Cytokine gene polymorphisms affect reactivation of cytomegalovirus in patients with cancer. Cytokine. 2012; 60(2):417-22. DOI: 10.1016/j.cyto.2012.07.018. View

18.

de Rham C, Hadaya K, Bandelier C, Ferrari-Lacraz S, Villard J . Expression of killer cell immunoglobulin-like receptors (KIRs) by natural killer cells during acute CMV infection after kidney transplantation. Transpl Immunol. 2014; 31(3):157-64. DOI: 10.1016/j.trim.2014.08.002. View

19.

Gallez-Hawkins G, Franck A, Li X, Thao L, Oki A, Gendzekhadze K . Expression of activating KIR2DS2 and KIR2DS4 genes after hematopoietic cell transplantation: relevance to cytomegalovirus infection. Biol Blood Marrow Transplant. 2011; 17(11):1662-72. PMC: 3199314. DOI: 10.1016/j.bbmt.2011.04.008. View

20.

Foley B, De Santis D, van Beelen E, Lathbury L, Christiansen F, Witt C . The reactivity of Bw4+ HLA-B and HLA-A alleles with KIR3DL1: implications for patient and donor suitability for haploidentical stem cell transplantations. Blood. 2008; 112(2):435-43. DOI: 10.1182/blood-2008-01-132902. View