Skip to main content
Top
Published in: Annals of Hematology 8/2013

01-08-2013 | Original Article

Impact of NOD2 polymorphisms on infectious complications following chemotherapy in patients with acute myeloid leukaemia

Authors: Olaposi Yomade, Bärbel Spies-Weisshart, Anita Glaser, Ulf Schnetzke, Andreas Hochhaus, Sebastian Scholl

Published in: Annals of Hematology | Issue 8/2013

Login to get access

Abstract

We sought to investigate the relationship between polymorphisms of the NOD2 gene and infectious complications following intensive induction chemotherapy in patients with acute myeloid leukaemia (AML). We hypothesised that single nucleotide polymorphisms (SNPs) of the NOD2 gene are associated with a higher rate of infections during the phase of severe neutropenia. In 131 AML patients receiving induction therapy, the presence of the three most frequent polymorphisms of NOD2 (Arg702Trp, Gly908Arg, Leu1007fsinsC) was analysed. SNP analyses by means of genomic PCR incorporating fluorescence-labelled probes with characteristic melting curves were performed using the LightCycler platform. Our data suggest a significantly lower probability of mucositis or enteritis in AML patients lacking any of the three evaluated NOD2 polymorphisms. Furthermore, bloodstream cultures of AML patients carrying either a missense or a frameshift mutation of NOD2 were significantly more frequently tested positive concerning Streptococcus spp. In contrast, the presence of NOD2 polymorphisms had no impact on such important infectious complications as systemic inflammatory response syndrome or sepsis, the rate of central venous catheter infections or the incidence of pneumonia including fungal infections. Our data represent one of the first reports investigating the impact of polymorphisms of the innate immune system on infectious complications in patients with neutropenia following chemotherapy. A correlation between NOD2 polymorphisms and infectious events in AML patients is demonstrated.
Literature
1.
go back to reference Damon LE et al (1994) Post-remission cytopenias following intense induction chemotherapy for acute myeloid leukemia. Leukemia 8(4):535–41PubMed Damon LE et al (1994) Post-remission cytopenias following intense induction chemotherapy for acute myeloid leukemia. Leukemia 8(4):535–41PubMed
2.
go back to reference Gupta A et al (2010) Infections in acute myeloid leukemia: an analysis of 382 febrile episodes. Med Oncol 27(4):1037–45PubMedCrossRef Gupta A et al (2010) Infections in acute myeloid leukemia: an analysis of 382 febrile episodes. Med Oncol 27(4):1037–45PubMedCrossRef
3.
go back to reference Syrjala H et al (2010) Blood stream infections during chemotherapy-induced neutropenia in adult patients with acute myeloid leukemia: treatment cycle matters. Eur J Clin Microbiol Infect Dis 29(10):1211–8PubMedCrossRef Syrjala H et al (2010) Blood stream infections during chemotherapy-induced neutropenia in adult patients with acute myeloid leukemia: treatment cycle matters. Eur J Clin Microbiol Infect Dis 29(10):1211–8PubMedCrossRef
4.
go back to reference Specchia G et al (2003) Pneumonia in acute leukemia patients during induction therapy: experience in a single institution. Leuk Lymphoma 44(1):97–101PubMedCrossRef Specchia G et al (2003) Pneumonia in acute leukemia patients during induction therapy: experience in a single institution. Leuk Lymphoma 44(1):97–101PubMedCrossRef
5.
go back to reference Brown KL et al (2007) Complexities of targeting innate immunity to treat infection. Trends Immunol 28(6):260–6PubMedCrossRef Brown KL et al (2007) Complexities of targeting innate immunity to treat infection. Trends Immunol 28(6):260–6PubMedCrossRef
6.
go back to reference Ito T et al (2012) Notch system in the linkage of innate and adaptive immunity. J Leukoc Biol 92(1):59–65PubMedCrossRef Ito T et al (2012) Notch system in the linkage of innate and adaptive immunity. J Leukoc Biol 92(1):59–65PubMedCrossRef
7.
go back to reference Elphick DA, Mahida YR (2005) Paneth cells: their role in innate immunity and inflammatory disease. Gut 54(12):1802–9PubMedCrossRef Elphick DA, Mahida YR (2005) Paneth cells: their role in innate immunity and inflammatory disease. Gut 54(12):1802–9PubMedCrossRef
8.
go back to reference Selsted ME, Ouellette AJ (2005) Mammalian defensins in the antimicrobial immune response. Nat Immunol 6(6):551–7PubMedCrossRef Selsted ME, Ouellette AJ (2005) Mammalian defensins in the antimicrobial immune response. Nat Immunol 6(6):551–7PubMedCrossRef
9.
go back to reference Gutierrez O et al (2002) Induction of Nod2 in myelomonocytic and intestinal epithelial cells via nuclear factor-kappa B activation. J Biol Chem 277(44):41701–5PubMedCrossRef Gutierrez O et al (2002) Induction of Nod2 in myelomonocytic and intestinal epithelial cells via nuclear factor-kappa B activation. J Biol Chem 277(44):41701–5PubMedCrossRef
10.
go back to reference Lala S et al (2003) Crohn's disease and the NOD2 gene: a role for Paneth cells. Gastroenterology 125(1):47–57PubMedCrossRef Lala S et al (2003) Crohn's disease and the NOD2 gene: a role for Paneth cells. Gastroenterology 125(1):47–57PubMedCrossRef
11.
go back to reference Girardin SE et al (2003) Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 278(11):8869–72PubMedCrossRef Girardin SE et al (2003) Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 278(11):8869–72PubMedCrossRef
12.
go back to reference Ogura Y et al (2001) Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem 276(7):4812–8PubMedCrossRef Ogura Y et al (2001) Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem 276(7):4812–8PubMedCrossRef
13.
go back to reference Hugot JP et al (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411(6837):599–603PubMedCrossRef Hugot JP et al (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411(6837):599–603PubMedCrossRef
14.
go back to reference Ogura Y et al (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411(6837):603–6PubMedCrossRef Ogura Y et al (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411(6837):603–6PubMedCrossRef
15.
go back to reference Li J et al (2004) Regulation of IL-8 and IL-1beta expression in Crohn's disease associated NOD2/CARD15 mutations. Hum Mol Genet 13(16):1715–25PubMedCrossRef Li J et al (2004) Regulation of IL-8 and IL-1beta expression in Crohn's disease associated NOD2/CARD15 mutations. Hum Mol Genet 13(16):1715–25PubMedCrossRef
16.
go back to reference Netea MG et al (2005) NOD2 3020insC mutation and the pathogenesis of Crohn's disease: impaired IL-1beta production points to a loss-of-function phenotype. Neth J Med 63(8):305–8PubMed Netea MG et al (2005) NOD2 3020insC mutation and the pathogenesis of Crohn's disease: impaired IL-1beta production points to a loss-of-function phenotype. Neth J Med 63(8):305–8PubMed
17.
go back to reference Kobayashi KS et al (2005) Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307(5710):731–4PubMedCrossRef Kobayashi KS et al (2005) Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307(5710):731–4PubMedCrossRef
18.
go back to reference Uehara A et al (2007) Various human epithelial cells express functional Toll-like receptors, NOD1 and NOD2 to produce anti-microbial peptides, but not proinflammatory cytokines. Mol Immunol 44(12):3100–11PubMedCrossRef Uehara A et al (2007) Various human epithelial cells express functional Toll-like receptors, NOD1 and NOD2 to produce anti-microbial peptides, but not proinflammatory cytokines. Mol Immunol 44(12):3100–11PubMedCrossRef
19.
go back to reference Wehkamp J et al (2004) NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression. Gut 53(11):1658–64PubMedCrossRef Wehkamp J et al (2004) NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression. Gut 53(11):1658–64PubMedCrossRef
20.
go back to reference Bevins CL, Stange EF, Wehkamp J (2009) Decreased Paneth cell defensin expression in ileal Crohn's disease is independent of inflammation, but linked to the NOD2 1007fs genotype. Gut 58(6):882–3, discussion 883–4PubMed Bevins CL, Stange EF, Wehkamp J (2009) Decreased Paneth cell defensin expression in ileal Crohn's disease is independent of inflammation, but linked to the NOD2 1007fs genotype. Gut 58(6):882–3, discussion 883–4PubMed
21.
go back to reference Van der Graaf CA et al (2006) Toll-like receptor 4 Asp299Gly/Thr399Ile polymorphisms are a risk factor for Candida bloodstream infection. Eur Cytokine Netw 17(1):29–34PubMed Van der Graaf CA et al (2006) Toll-like receptor 4 Asp299Gly/Thr399Ile polymorphisms are a risk factor for Candida bloodstream infection. Eur Cytokine Netw 17(1):29–34PubMed
22.
go back to reference Wurfel MM et al (2008) Toll-like receptor 1 polymorphisms affect innate immune responses and outcomes in sepsis. Am J Respir Crit Care Med 178(7):710–20PubMedCrossRef Wurfel MM et al (2008) Toll-like receptor 1 polymorphisms affect innate immune responses and outcomes in sepsis. Am J Respir Crit Care Med 178(7):710–20PubMedCrossRef
23.
go back to reference Brenmoehl J et al (2007) Genetic variants in the NOD2/CARD15 gene are associated with early mortality in sepsis patients. Intensive Care Med 33(9):1541–8PubMedCrossRef Brenmoehl J et al (2007) Genetic variants in the NOD2/CARD15 gene are associated with early mortality in sepsis patients. Intensive Care Med 33(9):1541–8PubMedCrossRef
24.
go back to reference Klostergaard A et al (2010) Sepsis in acute myeloid leukaemia patients receiving high-dose chemotherapy: no impact of chitotriosidase and mannose-binding lectin polymorphisms. Eur J Haematol 85(1):58–64PubMed Klostergaard A et al (2010) Sepsis in acute myeloid leukaemia patients receiving high-dose chemotherapy: no impact of chitotriosidase and mannose-binding lectin polymorphisms. Eur J Haematol 85(1):58–64PubMed
25.
go back to reference Choi EH et al (2005) Common polymorphisms in critical genes of innate immunity do not contribute to the risk for chronic disseminated candidiasis in adult leukemia patients. Med Mycol 43(4):349–53PubMedCrossRef Choi EH et al (2005) Common polymorphisms in critical genes of innate immunity do not contribute to the risk for chronic disseminated candidiasis in adult leukemia patients. Med Mycol 43(4):349–53PubMedCrossRef
26.
go back to reference Holler E et al (2004) Both donor and recipient NOD2/CARD15 mutations associate with transplant-related mortality and GvHD following allogeneic stem cell transplantation. Blood 104(3):889–94PubMedCrossRef Holler E et al (2004) Both donor and recipient NOD2/CARD15 mutations associate with transplant-related mortality and GvHD following allogeneic stem cell transplantation. Blood 104(3):889–94PubMedCrossRef
27.
go back to reference Elmaagacli AH et al (2006) Mutations in innate immune system NOD2/CARD 15 and TLR-4 (Thr399Ile) genes influence the risk for severe acute graft-versus-host disease in patients who underwent an allogeneic transplantation. Transplantation 81(2):247–54PubMedCrossRef Elmaagacli AH et al (2006) Mutations in innate immune system NOD2/CARD 15 and TLR-4 (Thr399Ile) genes influence the risk for severe acute graft-versus-host disease in patients who underwent an allogeneic transplantation. Transplantation 81(2):247–54PubMedCrossRef
29.
go back to reference Becker C et al (2004) 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 Annual Meeting Abstracts 104(11):880 Becker C et al (2004) 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 Annual Meeting Abstracts 104(11):880
30.
go back to reference Basara N et al (2009) 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 23(4):635–40PubMedCrossRef Basara N et al (2009) 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 23(4):635–40PubMedCrossRef
31.
go back to reference Ruegg C et al (2004) Detection of the Arg702Trp, Gly908Arg and Leu1007fsinsC polymorphisms of the NOD2/CARD15 gene by real-time PCR with melting curve analysis. Clin Chem Lab Med 42(5):494–8PubMedCrossRef Ruegg C et al (2004) Detection of the Arg702Trp, Gly908Arg and Leu1007fsinsC polymorphisms of the NOD2/CARD15 gene by real-time PCR with melting curve analysis. Clin Chem Lab Med 42(5):494–8PubMedCrossRef
32.
go back to reference Reinhart K et al. (2010) 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 8: p Doc14 Reinhart K et al. (2010) 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 8: p Doc14
33.
go back to reference De Pauw B et al (2008) Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 46(12):1813–21PubMedCrossRef De Pauw B et al (2008) Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 46(12):1813–21PubMedCrossRef
34.
go back to reference Lecat A, Piette J, Legrand-Poels S (2010) The protein Nod2: an innate receptor more complex than previously assumed. Biochem Pharmacol 80(12):2021–31PubMedCrossRef Lecat A, Piette J, Legrand-Poels S (2010) The protein Nod2: an innate receptor more complex than previously assumed. Biochem Pharmacol 80(12):2021–31PubMedCrossRef
35.
go back to reference Kaser A, Niederreiter L, Blumberg RS (2011) Genetically determined epithelial dysfunction and its consequences for microflora-host interactions. Cell Mol Life Sci 68(22):3643–9PubMedCrossRef Kaser A, Niederreiter L, Blumberg RS (2011) Genetically determined epithelial dysfunction and its consequences for microflora-host interactions. Cell Mol Life Sci 68(22):3643–9PubMedCrossRef
36.
go back to reference Cuthbert AP et al (2002) The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease. Gastroenterology 122(4):867–74PubMedCrossRef Cuthbert AP et al (2002) The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease. Gastroenterology 122(4):867–74PubMedCrossRef
37.
go back to reference Camera A et al (2003) Intestinal toxicity during induction chemotherapy with cytarabine-based regimens in adult acute myeloid leukemia. Hematol J 4(5):346–50PubMedCrossRef Camera A et al (2003) Intestinal toxicity during induction chemotherapy with cytarabine-based regimens in adult acute myeloid leukemia. Hematol J 4(5):346–50PubMedCrossRef
38.
go back to reference Hogan WJ et al (2002) Neutropenic colitis after treatment of acute myelogenous leukemia with idarubicin and cytosine arabinoside. Mayo Clin Proc 77(8):760–2PubMedCrossRef Hogan WJ et al (2002) Neutropenic colitis after treatment of acute myelogenous leukemia with idarubicin and cytosine arabinoside. Mayo Clin Proc 77(8):760–2PubMedCrossRef
39.
go back to reference Opitz B et al (2004) Nucleotide-binding oligomerization domain proteins are innate immune receptors for internalized Streptococcus pneumoniae. J Biol Chem 279(35):36426–32PubMedCrossRef Opitz B et al (2004) Nucleotide-binding oligomerization domain proteins are innate immune receptors for internalized Streptococcus pneumoniae. J Biol Chem 279(35):36426–32PubMedCrossRef
40.
go back to reference Koppe U, Suttorp N, Opitz B (2012) Recognition of Streptococcus pneumoniae by the innate immune system. Cell Microbiol 14(4):460–6PubMedCrossRef Koppe U, Suttorp N, Opitz B (2012) Recognition of Streptococcus pneumoniae by the innate immune system. Cell Microbiol 14(4):460–6PubMedCrossRef
41.
go back to reference Henckaerts L et al (2009) Polymorphisms in innate immunity genes predispose to bacteremia and death in the medical intensive care unit. Crit Care Med 37(1):192–201, e1-3PubMedCrossRef Henckaerts L et al (2009) Polymorphisms in innate immunity genes predispose to bacteremia and death in the medical intensive care unit. Crit Care Med 37(1):192–201, e1-3PubMedCrossRef
42.
go back to reference Wong M et al (2012) Mannose-binding lectin 2 polymorphisms do not influence frequency or type of infection in adults with chemotherapy induced neutropaenia. PLoS One 7(2):e30819PubMedCrossRef Wong M et al (2012) Mannose-binding lectin 2 polymorphisms do not influence frequency or type of infection in adults with chemotherapy induced neutropaenia. PLoS One 7(2):e30819PubMedCrossRef
Metadata
Title
Impact of NOD2 polymorphisms on infectious complications following chemotherapy in patients with acute myeloid leukaemia
Authors
Olaposi Yomade
Bärbel Spies-Weisshart
Anita Glaser
Ulf Schnetzke
Andreas Hochhaus
Sebastian Scholl
Publication date
01-08-2013
Publisher
Springer Berlin Heidelberg
Published in
Annals of Hematology / Issue 8/2013
Print ISSN: 0939-5555
Electronic ISSN: 1432-0584
DOI
https://doi.org/10.1007/s00277-013-1734-0

Other articles of this Issue 8/2013

Annals of Hematology 8/2013 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine