Abstract
Infectious complications continue to be one of the major causes of morbidity and mortality in patients with acute myeloid leukemia (AML). Several single-nucleotide polymorphisms (SNPs) of Toll-like receptors (TLRs) can affect the genetic susceptibility to infections or even sepsis. We sought to investigate the impact of different SNPs on the incidence of developing sepsis and pneumonia in patients with newly diagnosed AML following induction chemotherapy. We analyzed three SNPs in the TLR2 (Arg753Gln) and TLR4 (Asp299Gly and Thr399Ile) gene in a cohort of 155 patients with AML who received induction chemotherapy. The risk of developing sepsis and pneumonia was assessed by multiple logistic regression analyses. The presence of the TLR2 Arg753Gln polymorphism was significantly associated with pneumonia in AML patients (odds ratio (OR): 10.78; 95% confidence interval (CI): 2.0–58.23; P=0.006). Furthermore, the cosegregating TLR4 polymorphisms Asp299Gly and Thr399Ile were independent risk factors for the development of both sepsis and pneumonia (OR: 3.55; 95% CI: 1.21–10.4, P=0.021 and OR: 3.57, 95% CI: 1.3–9.86, P=0.014, respectively). To our best knowledge, this study represents the first analysis demonstrating that polymorphisms of TLR2 and TLR4 influence the risk of infectious complications in patients with AML undergoing induction chemotherapy.
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References
Gupta A, Singh M, Singh H, Kumar L, Sharma A, Bakhshi S et al. Infections in acute myeloid leukemia: an analysis of 382 febrile episodes. Med Oncol 2010; 27: 1037–1045.
Syrjala H, Ohtonen P, Kinnunen U, Raty R, Elonen E, Nousiainen T et al. Blood stream infections during chemotherapy-induced neutropenia in adult patients with acute myeloid leukemia: treatment cycle matters. Eur J Clin Microbiol Infect Dis 2010; 29: 1211–1218.
Specchia G, Pastore D, Carluccio P, Mele G, Montagna MT, Liso A et al. Pneumonia in acute leukemia patients during induction therapy: experience in a single institution. Leuk Lymphoma 2003; 44: 97–101.
Hamalainen S, Kuittinen T, Matinlauri I, Nousiainen T, Koivula I, Jantunen E . Neutropenic fever and severe sepsis in adult acute myeloid leukemia (AML) patients receiving intensive chemotherapy: causes and consequences. Leuk Lymphoma 2008; 49: 495–501.
Rossini F, Verga M, Pioltelli P, Giltri G, Sancassani V, Pogliani EM et al. Incidence and outcome of pneumonia in patients with acute leukemia receiving first induction therapy with anthracycline-containing regimens. Haematologica 2000; 85: 1255–1260.
Schenten D, Medzhitov R . The control of adaptive immune responses by the innate immune system. Adv Immunol 2011; 109: 87–124.
Brown KL, Cosseau C, Gardy JL, Hancock RE . Complexities of targeting innate immunity to treat infection. Trends Immunol 2007; 28: 260–266.
Kawai T, Akira S . The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010; 11: 373–384.
Netea MG, Van der Graaf C, Van der Meer JW, Kullberg BJ . Recognition of fungal pathogens by Toll-like receptors. Eur J Clin Microbiol Infect Dis 2004; 23: 672–676.
Ferwerda B, McCall MB, Verheijen K, Kullberg BJ, van der Ven AJ, Van der Meer JW et al. Functional consequences of toll-like receptor 4 polymorphisms. Mol Med 2008; 14: 346–352.
Ohto U, Yamakawa N, Akashi-Takamura S, Miyake K, Shimizu T . Structural analyses of human Toll-like receptor 4 polymorphisms D299G and T399I. J Biol Chem 2012; 287: 40611–40617.
Nachtigall I, Tamarkin A, Tafelski S, Weimann A, Rothbart A, Heim S et al. Polymorphisms of the toll-like receptor 2 and 4 genes are associated with faster progression and a more severe course of sepsis in critically ill patients. J Int Med Res 2014; 42: 93–110.
Sampath V, Mulrooney NP, Garland JS, He J, Patel AL, Cohen JD et al. Toll-like receptor genetic variants are associated with Gram-negative infections in VLBW infants. J Perinatol 2013; 33: 772–777.
Papadopoulos AI, Ferwerda B, Antoniadou A, Sakka V, Galani L, Kavatha D et al. Association of toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms with increased infection risk in patients with advanced HIV-1 infection. Clin Infect Dis 2010; 51: 242–247.
Van der Graaf CA, Netea MG, Morre SA, Den Heijer M, Verweij PE, Van der Meer JW et al. Toll-like receptor 4 Asp299Gly/Thr399Ile polymorphisms are a risk factor for Candida bloodstream infection. Eur Cytokine Netw 2006; 17: 29–34.
Bochud PY, Chien JW, Marr KA, Leisenring WM, Upton A, Janer M et al. Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med 2008; 359: 1766–1777.
Xiong Y, Song C, Snyder GA, Sundberg EJ, Medvedev AE . R753Q polymorphism inhibits Toll-like receptor (TLR) 2 tyrosine phosphorylation, dimerization with TLR6, and recruitment of myeloid differentiation primary response protein 88. J Biol Chem 2012; 287: 38327–38337.
Lee SO, Brown RA, Kang SH, Abdel-Massih RC, Razonable RR . Toll-like receptor 2 polymorphism and Gram-positive bacterial infections after liver transplantation. Liver Transpl 2011; 17: 1081–1088.
Sutherland AM, Walley KR, Russell JA . Polymorphisms in CD14, mannose-binding lectin, and Toll-like receptor-2 are associated with increased prevalence of infection in critically ill adults. Crit Care Med 2005; 33: 638–644.
Kang SH, Abdel-Massih RC, Brown RA, Dierkhising RA, Kremers WK, Razonable RR . Homozygosity for the toll-like receptor 2 R753Q single-nucleotide polymorphism is a risk factor for cytomegalovirus disease after liver transplantation. J Infect Dis 2012; 205: 639–646.
Brown RA, Gralewski JH, Eid AJ, Knoll BM, Finberg RW, Razonable RR . R753Q single-nucleotide polymorphism impairs toll-like receptor 2 recognition of hepatitis C virus core and nonstructural 3 proteins. Transplantation 2010; 89: 811–815.
Klostergaard A, Steffensen R, Moller JK, Peterslund N, Juhl-Christensen C, Molle I . Sepsis in acute myeloid leukaemia patients receiving high-dose chemotherapy: no impact of chitotriosidase and mannose-binding lectin polymorphisms. Eur J Haematol 2010; 85: 58–64.
Choi EH, Taylor JG, Foster CB, Walsh TJ, Anttila VJ, Ruutu T et al. Common polymorphisms in critical genes of innate immunity do not contribute to the risk for chronic disseminated candidiasis in adult leukemia patients. Med Mycol 2005; 43: 349–353.
Yomade O, Spies-Weisshart B, Glaser A, Schnetzke U, Hochhaus A, Scholl S . Impact of NOD2 polymorphisms on infectious complications following chemotherapy in patients with acute myeloid leukaemia. Ann Hematol 2013; 92: 1071–1077.
Pabst S, Yenice V, Lennarz M, Tuleta I, Nickenig G, Gillissen A et al. Toll-like receptor 2 gene polymorphisms Arg677Trp and Arg753Gln in chronic obstructive pulmonary disease. Lung 2009; 187: 173–178.
Schroder NW, Hermann C, Hamann L, Gobel UB, Hartung T, Schumann RR . High frequency of polymorphism Arg753Gln of the Toll-like receptor-2 gene detected by a novel allele-specific PCR. J Mol Med (Berl) 2003; 81: 368–372.
Reinhart K, Brunkhorst FM, Bone HG, Bardutzky J, Dempfle CE, Forst H et al. Prevention, diagnosis, therapy and follow-up care of sepsis: 1st revision of S-2k guidelines of the German Sepsis Society (Deutsche Sepsis-Gesellschaft e.V. (DSG)) and the German Interdisciplinary Association of Intensive Care and Emergency Medicine (Deutsche Interdisziplinare Vereinigung fur Intensiv- und Notfallmedizin (DIVI)). Ger Med Sci 2010; 8: Doc14.
Ahmad-Nejad P, Denz C, Zimmer W, Wacker J, Bugert P, Weiss C et al. The presence of functionally relevant toll-like receptor polymorphisms does not significantly correlate with development or outcome of sepsis. Genet Test Mol Biomarkers 2011; 15: 645–651.
Garnacho-Montero J, Garcia-Cabrera E, Jimenez-Alvarez R, Diaz-Martin A, Revuelto-Rey J, Aznar-Martin J et al. Genetic variants of the MBL2 gene are associated with mortality in pneumococcal sepsis. Diagn Microbiol Infect Dis 2012; 73: 39–44.
Arcaroli J, Silva E, Maloney JP, He Q, Svetkauskaite D, Murphy JR et al. Variant IRAK-1 haplotype is associated with increased nuclear factor-kappaB activation and worse outcomes in sepsis. Am J Respir Crit Care Med 2006; 173: 1335–1341.
Kumpf O, Giamarellos-Bourboulis EJ, Koch A, Hamann L, Mouktaroudi M, Oh DY et al. Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release: an observational study in three cohorts. Crit Care 2010; 14: R103.
Abreu MT . Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol 2010; 10: 131–144.
Chen LW, Chen PH, Hsu CM . Commensal microflora contribute to host defense against Escherichia coli pneumonia through Toll-like receptors. Shock 2011; 36: 67–75.
Yamamoto K, Ferrari JD, Cao Y, Ramirez MI, Jones MR, Quinton LJ et al. Type I alveolar epithelial cells mount innate immune responses during pneumococcal pneumonia. J Immunol 2012; 189: 2450–2459.
Schurr JR, Young E, Byrne P, Steele C, Shellito JE, Kolls JK . Central role of toll-like receptor 4 signaling and host defense in experimental pneumonia caused by Gram-negative bacteria. Infect Immun 2005; 73: 532–545.
Tang L, Li Q, Bai J, Zhang H, Lu Y, Ma S . Severe pneumonia mortality in elderly patients is associated with downregulation of Toll-like receptors 2 and 4 on monocytes. Am J Med Sci 2014; 347: 34–41.
Basara N, Schulze A, Wedding U, Mohren M, Gerhardt A, Junghanss C et al. Early related or unrelated haematopoietic cell transplantation results in higher overall survival and leukaemia-free survival compared with conventional chemotherapy in high-risk acute myeloid leukaemia patients in first complete remission. Leukemia 2009; 23: 635–640.
Becker C, Ali HA, Krahl R, Poenisch W, Wedding U, Fiedler F et al. High complete remission rate in patients with acute myeloid leukemia (AML) above the Age of 60 Years: A Report of the AML97#38 Study of the East German Hematology and Oncology Study Group. ASH Annu Meet Abstr 2004; 104: Abstract 880.
Brothman AR, Persons DL, Shaffer LG . Nomenclature evolution: changes in the ISCN from the 2005 to the 2009 edition. Cytogenet Genome Res 2009; 127: 1–4.
Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010; 115: 453–474.
Acknowledgements
This work was supported by the ‘Förderprogramm Infektiologie 2013’ as a grant from Gilead (Munich, Germany).
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Schnetzke, U., Spies-Weisshart, B., Yomade, O. et al. Polymorphisms of Toll-like receptors (TLR2 and TLR4) are associated with the risk of infectious complications in acute myeloid leukemia. Genes Immun 16, 83–88 (2015). https://doi.org/10.1038/gene.2014.67
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DOI: https://doi.org/10.1038/gene.2014.67
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